Redefined role of angiogenesis in the pathogenesis of dural arteriovenous malformations

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✓ To investigate the role of angiogenesis in the pathogenesis of dural arteriovenous malformations (AVMs), 40 rats underwent common carotid artery—external jugular vein (CCA-EJV) anastomosis, bipolar coagulation of the vein draining the transverse sinus, and sagittal sinus thrombosis to induce venous hypertension. Fifteen rats underwent a similar surgical procedure, but venous hypertension was not induced. The 55 rats were divided into seven groups. Four groups, each containing 10 rats, underwent induced venous hypertension. The other three groups, each containing five rats, did not undergo induced venous hypertension. After 1, 2, or 3 weeks, dura mater was obtained from one group of hypertensive rats and from one group of nonhypertensive rats and was assayed for angiogenic activity (rabbit cornea bioassay). The remaining group of 10 hypertensive rats was not assayed to determine if sampling affected dural AVM formation. Unlike rats without CCA-EJV anastomosis, rats with CCA-EJV anastomosis had significantly increased postoperative sagittal sinus pressures (p < 0.0001). Mean angiogenesis indices were significantly greater in rats with venous hypertension than in rats without venous hypertension (p = 0.004). Dural AVMs formed in 42% of the 55 rats and facial AVMs formed in 51%. Angiogenic activity correlated positively with venous hypertension (ρ = 0.74). Development of dural AVMs correlated positively with both venous hypertension (p = 0.0009) and angiogenic activity (p = 0.04). These data indicate that venous hypertension may induce angiogenic activity either directly or indirectly by decreasing cerebral perfusion and increasing ischemia, and that dural AVM formation may be the result of aberrant angiogenesis.

Abstract

✓ To investigate the role of angiogenesis in the pathogenesis of dural arteriovenous malformations (AVMs), 40 rats underwent common carotid artery—external jugular vein (CCA-EJV) anastomosis, bipolar coagulation of the vein draining the transverse sinus, and sagittal sinus thrombosis to induce venous hypertension. Fifteen rats underwent a similar surgical procedure, but venous hypertension was not induced. The 55 rats were divided into seven groups. Four groups, each containing 10 rats, underwent induced venous hypertension. The other three groups, each containing five rats, did not undergo induced venous hypertension. After 1, 2, or 3 weeks, dura mater was obtained from one group of hypertensive rats and from one group of nonhypertensive rats and was assayed for angiogenic activity (rabbit cornea bioassay). The remaining group of 10 hypertensive rats was not assayed to determine if sampling affected dural AVM formation. Unlike rats without CCA-EJV anastomosis, rats with CCA-EJV anastomosis had significantly increased postoperative sagittal sinus pressures (p < 0.0001). Mean angiogenesis indices were significantly greater in rats with venous hypertension than in rats without venous hypertension (p = 0.004). Dural AVMs formed in 42% of the 55 rats and facial AVMs formed in 51%. Angiogenic activity correlated positively with venous hypertension (ρ = 0.74). Development of dural AVMs correlated positively with both venous hypertension (p = 0.0009) and angiogenic activity (p = 0.04). These data indicate that venous hypertension may induce angiogenic activity either directly or indirectly by decreasing cerebral perfusion and increasing ischemia, and that dural AVM formation may be the result of aberrant angiogenesis.

Dural arteriovenous malformations (AVMs) appear to be acquired rather than congenital lesions.2,4,7,8,13,21,24,26,47,49,64 Dural AVMs may arise from intrinsic arteriovenous communications in the dura mater that open to form fistulas that shunt arterial blood flow into the dural sinuses.2–4,13,32,55 Alternatively, the increased venous pressure associated with sinus thrombosis and venous outflow obstruction could open these channels.21 Dysauto-regulatory vasodilation in response to venous hypertension may convert previously normal capillaries into arteriovenous fistulas and dural AVMs.64 These hypotheses share the notion that dural AVMs arise from preexisting vascular channels in the dura. However, dural AVMs could also arise from newly formed blood vessels, or angiogenesis, as part of the inflammatory process that organizes and recanalizes thrombosed sinuses.7,8,24,26,62 These hypotheses, however, are derived only from angiographic data and pathological specimens obtained in humans.

Rat models have confirmed that venous hypertension64 and sagittal sinus thrombosis24 elicit the formation of dural AVMs. Such animal models enable the study of events leading to the formation of dural AVMs before gross histological changes are apparent—a window of observation lacking in the clinical setting. No laboratory investigation has thus far demonstrated angiogenic activity in the development of dural AVMs: the notion has been purely speculative. This study, however, provides the first experimental evidence supporting angiogenesis as a mechanism of dural AVM formation.

Materials and Methods

Animal Preparation

Fifty-five Sprague—Dawley rats, each weighing between 250 and 350 g, were used in the study. To exclude any potential effects of hormones on dural AVM formation, only male rats were used.37,65

Rats were anesthetized with an intramuscular injection of a mixture of ketamine (10 ml), xylazine (1.4 ml), and acepromazine (2 ml) at a dose of 0.6 ml/kg. Additional doses were given during the surgical procedure as needed. All surgical procedures were performed using standard sterile technique.

Surgical Technique

Forty rats underwent a surgical procedure to induce venous hypertension, venous outflow occlusion, and sagittal sinus thrombosis.24 Through an anterior midline cervical incision, the right proximal common carotid artery (CCA) was anastomosed to the right distal external jugular vein (EJV) (Fig. 1). An end-to-end anastomosis was performed, with the aid of an operating microscope, by using No. 10-0 monofilament nylon sutured in a continuous fashion. Through a second incision made below the left ear, the vein draining the transverse sinus was exposed and coagulated with bipolar cauterization. Through a third scalp incision made in the midline over the sagittal suture, the parietal skull overlying the sagittal sinus and adjacent dura mater was thinned using a drill (B3D diamond bit; Midas Rex Pneumatic Tools, Inc., Fort Worth, TX) and removed. The sagittal sinus was thrombosed by incising the sinus wall, packing it with Surgicel hemostatic agent, and applying pressure for 10 minutes. All wounds were irrigated with sterile saline, and the incisions were closed with continuous No. 5-0 nylon suture.

Fig. 1.
Fig. 1.

Illustrations showing the surgical procedures that induced (left) or did not induce (right) venous hypertension in rats.

In contrast, 15 rats underwent a similar surgical procedure but venous hypertension was not induced. The right CCA and EJV were exposed; however, they were occluded with bipolar coagulation and divided rather than anastomosed. The vein draining the transverse sinus was occluded and the sagittal sinus was thrombosed, as in the rats with hypertension.

Mean arterial pressure (MAP) and sagittal sinus (SS) pressure were measured in all rats before and after the surgical procedures, as described by Herman and colleagues.24

Rabbit Cornea Assay

After 1, 2, or 3 weeks, one group of hypertensive and one group of nonhypertensive rats underwent dural sampling. (The remaining 10 rats with venous hypertension did not undergo dural sampling so that they could serve as controls for the effects of sampling on dural AVM formation.) The previous scalp incision was reopened and a 2 × 2—mm piece of parietal dura mater adjacent to the sagittal sinus thrombosis was harvested from both left and right sides. The scalp incision was then closed with continuous No. 5-0 nylon suture.

The dural specimens were immediately implanted in a rabbit cornea, using a well-described angiogenesis assay.19 Briefly, New Zealand white rabbits were anesthetized with the ketamine-xylazine-acepromazine mixture (0.6 ml/kg). Each eye was proptosed from the orbit, and a sterile rubber drape was placed over the eye to retract the lids. A superficial incision was made in the cornea, into but not through the stroma. A Rhoton No. 6 dissector was inserted tangentially in this stromal layer to create a pocket whose base was located 1 mm from the cornea—sclera junction. A dural specimen was harvested and immediately inserted into the bottom of the pocket. Specimens taken from a given rat were inserted into their own corneal pockets in opposite eyes of the rabbit. After implantation, the rubber drape was removed and the eye was irrigated with sterile saline.

One week later, the rabbit corneas were examined under the operating microscope. An angiogenesis index63 was used to measure the angiogenic activity elicited by the dural implant. Vascular density was scored according to a 4-point scale: 0, no vessels; 1, one to 10 vessels; 2, more than 10 vessels, loosely packed so that the iris could be observed through gaps between the vessels; and 3, more than 10 vessels, tightly packed so that the iris could not be observed through gaps between the vessels. The length of the new blood vessels was measured from the cornea—sclera junction to the leading edge of the front of the vessels. The angiogenesis index was obtained by multiplying the vascular density score and the length of angiogenic vessels. The corneas were photographed at × 10 magnification, and the rabbits were killed with an overdose of sodium pentothal.

Angiographic Studies

Cerebral angiography was performed in all rats 3 months after their initial surgery. After appropriate anesthesia was induced in each animal, the previous cervical incision was reopened and the patency of the right CCA—EJV anastomosis was confirmed. The left CCA was cannulated with a 22-gauge catheter and secured with No. 4-0 nylon suture. Rapid sequence digital subtraction angiography was performed in anteroposterior and lateral views. The fistula was occluded with a 5-mm aneurysm clip during angiography. Contrast medium (Omnipaque, 0.3 ml) was injected for 1 second, and images were filmed until the venous phase was complete.

Angiograms were evaluated for the presence and location of dural AVMs and for the presence of feeding arteries, draining veins, facial AVMs, and sagittal sinus occlusion. Angiographic findings were graded according to a four-point scale: Grade 0, no AVM; Grade I, facial AVM; Grade II, dural AVM; and Grade III, facial and dural AVMs.

After angiography, the rats were killed with an overdose of sodium pentothal, except for the 10 control rats that had not undergone dural sampling. In these rats, the arteriotomy was repaired with No. 10-0 monofilament nylon suture and the CCA—EJV fistula was occluded to restore normal sinus pressure. The neck incision was then closed. The rats survived an additional month, after which another left CCA angiogram was obtained to assess whether the dural AVMs had regressed. After angiography, SS pressures were recorded and these rats were also killed.

Statistical Analysis

An independent t-test was used to detect differences between pre and postoperative SS pressures. Otherwise, a one-way analysis of variance was used to detect differences in SS pressures, angiogenesis index, and angiographic grade between two or more groups. The correlation between SS pressures and angiogenesis index was analyzed using a Spearman rank correlation coefficient, ρ (one-tailed test). After venous pressures were normalized in the 10 control rats, dural AVM regression was analyzed using a Wilcoxon signed rank test, W (one-tailed test). For all tests, the level of significance was set at p < 0.05.

Results
Hemodynamic Measurements

There was no difference in the mean preoperative SS pressures between the 40 rats with venous hypertension (4 mm Hg) and the 15 rats without venous hypertension (3.7 mm Hg) (Table 1). Postoperatively, however, the CCA—EJV anastomosis significantly raised SS pressures to a mean of 21.9 mm Hg in the 40 rats with venous hypertension compared to their preoperative baseline (t = 13.44, p < 0.0001). As expected, there was no significant change between preoperative and postoperative SS pressures in the rats without venous hypertension. The mean postoperative SS pressures in the 40 rats with venous hypertension was significantly greater than the mean postoperative SS pressures in the 15 rats without venous hypertension (p < 0.0001; F = 66.06). The differences in postoperative SS pressures were not statistically significant among either the four groups of rats with venous hypertension or among the three groups of rats without venous hypertension.

TABLE 1

Mean hemodynamic measurements in rats used in the dural AVM model*

Dural Sampling Interval/Animal GroupNo. of RatsMAP (mm Hg)Preop SSP (mm Hg)Postop SSP (mm Hg)Angiogenesis IndexAngiographic Grade
1 wk
 w/ VHTN1088.04.623.13.131.7
 w/o VHTN584.53.63.00.120
2 wks
 w/ VHTN1091.33.522.51.801.7
 w/o VHTN596.24.03.40.170
3 wks
 w/ VHTN1096.33.921.51.181.5
 w/o VHTN599.43.64.80.170
control group1093.84.120.7NA2.5
 w/ VHTN

NA = not applicable; SSP = SS pressure; VHTN = venous hypertension.

Angiogenic Activity

Examples of the angiogenic activity induced by the rat dural implants in the rabbit corneas are shown in Fig. 2. The mean angiogenesis indices assayed at 1, 2, and 3 weeks were 3.13, 1.8, and 1.18, respectively, for rats with venous hypertension. In contrast, the mean angiogenesis indices assayed at 1, 2, and 3 weeks were 0.12, 0.17, and 0.17, respectively, for rats without venous hypertension. The difference in the pooled mean angiogenic activity between rats with and without venous hypertension was statistically significant (p = 0.004; F = 9.19). Furthermore, angiogenic activity decreased over time (Fig. 3).

Fig. 2.
Fig. 2.

Photographs showing angiogenic activity of rat dura mater assayed in the rabbit cornea. Blood vessels grow from the cornea—sclera junction toward the implant in the corneal pocket. Upper Left: No vessels (angiogenesis index of 0). Upper Right: One to 10 vessels (angiogenesis index of 1). Lower Left: More than 10 vessels, loosely packed with the iris visible through gaps between the vessels (angiogenesis index of 2). Lower Right: More than 10 vessels, tightly packed with no gaps between the vessels (angiogenesis index of 3). Original magnification × 10.

Fig. 3.
Fig. 3.

Bar graph displaying angiogenic activity (average angiogenesis index) of dura sampled from rats with and without venous hypertension at 1, 2, and 3 weeks. Error bars depict the standard error of the mean.

Angiographic Findings

All but one of the 40 rats with venous hypertension had a patent CCA—EJV anastomosis 3 months after surgery (patency rate 98%). The arterialized EJV was markedly dilated in these 39 rats. The SS, which had been occluded in all 55 rats, remained angiographically occluded in 49 rats (89%) and recanalized with residual stenosis in six rats (11%). The stenosed SSs were observed in four rats with venous hypertension and in two rats without venous hypertension. The vein draining the transverse sinus remained occluded in all 55 rats.

In the 10 control rats with venous hypertension that did not undergo dural sampling, dural AVMs tended to form adjacent to the site of SS thrombosis, as reported previously.24 In all other rats, because this dura mater was harvested for the rabbit cornea assay, the dural AVMs tended to form anterior to the site of SS thrombosis (Fig. 4). Typically, dural AVMs were fed by meningeal branches of the pterygopalatine artery, which in humans originates from the internal maxillary artery of the external carotid system but in rats branches from the internal carotid artery.22 Typically, drainage coursed anteriorly through the inferior cerebral sinus and into the posterior facial vein.

Fig. 4.
Fig. 4.

Cerebral angiograms demonstrating the four angiographic grades. A and B: Anteroposterior (AP [A]) and lateral (B) angiograms obtained in nonhypertensive rat showing arterial anatomy (Grade 0). C: Lateral angiogram showing a facial AVM (arrowhead) located in the nose with a prominent early draining vein (arrow) (Grade I). D: An AP angiogram showing a dural AVM (arrowhead) and an abnormal early draining vein (arrow), anterior to the SS thrombosis, as it drains laterally into the inferior cerebral sinus and posterior facial vein; no facial AVM is seen (Grade II). E and F: An AP (E) and lateral (F) angiogram showing a facial and dural AVM (Grade III, arrowheads) and their associated draining veins (arrows).

Overall, dural AVMs formed in 23 (42%) of the 55 rats, and facial AVMs formed in 28 rats (51%). No vascular malformations were detected on angiography (Grade 0) in 22 rats (40%). Ten rats (18%) had only facial AVMs (Grade I); five rats (9%) had only dural AVMs (Grade II); and 18 rats (33%) had facial and dural AVMs (Grade III). None of the rats without venous hypertension formed either dural or facial AVMs. Among the 40 rats with venous hypertension, 57% formed dural AVMs and 70% formed facial AVMs.

The mean angiographic grades were 1.7, 1.7, and 1.5 for assays performed at 1, 2, and 3 weeks, respectively, for the rats with venous hypertension. The mean angiographic grade was 0 for the rats without venous hypertension, regardless of the time of sampling. The 10 hypertensive control rats that did not undergo dural sampling had a higher mean angiographic grade (2.5) than the rats in the other three hypertension groups; however, the difference was not statistically significant (p = 0.06; F = 3.78). This finding indicates that dural sampling may have decreased dural AVM formation but did not prevent it. The rate of dural AVM formation in the control group was 80% compared to 60%, 40%, and 50% in the rats with venous hypertension in which samples were obtained at 1, 2, and 3 weeks, respectively.

Statistical Correlations

Angiogenic activity correlated positively with SS pressure (ρ = 0.74). The development of a dural AVM also correlated with SS pressure. Rats with dural AVMs (Grades II and III) had significantly greater venous pressures than rats without angiographic abnormalities (Grade 0) (p = 0.0009; F = 8.04). There were no significant differences, however, between SS pressures in rats with facial AVMs (Grade I) and those in rats with dural AVMs (Grades II and III).

The development of a dural AVM correlated with angiogenic activity. The mean angiogenesis index for rats with dural AVMs (Grades II and III) was 2.3, which was significantly greater than the mean index of 1 for rats without dural AVMs (Grades 0 and I) (p = 0.04; F = 4.45).

Dural AVM Regression With Normal Sinus Pressures

Of the 10 control rats not assayed for angiogenic activity, eight formed dural AVMs at 3 months. One month after occlusion of the CCA—EJV anastomosis in these 10 rats, repeated angiography demonstrated that four dural AVMs had regressed and four had persisted. The two rats without dural AVMs never developed them. The mean angiographic grade of these 10 rats decreased significantly from 2.5 at 3 months to 1 at 4 months (p = 0.02; W = 21). The mean SS pressure of all 10 control rats at 4 months was 2.8 mm Hg, indicating that occlusion of the anastomosis restored venous pressures to normal.

Discussion

For the first time, the current study has demonstrated significant relationships between venous hypertension and angiogenic activity and between angiogenic activity and dural AVM formation. These results indicate a new angiogenesis hypothesis of dural AVM formation (Fig. 5). Briefly, venous hypertension induced by an obstruction to venous outflow, such as a sinus thrombus, would initiate the pathogenesis of dural AVMs. Venous hypertension reduces cerebral perfusion and might produce ischemia. Tissue hypoxia normally stimulates angiogenesis in an attempt to reverse the ischemia. Aberrant angiogenic activity by dural blood vessels would then lead to arteriovenous shunting into the dural sinuses and to dural AVM formation. Arterialization of the venous sinuses exacerbates venous hypertension and outflow occlusion, thereby creating a vicious circle that would enlarge the dural AVM and lead to a more dangerous clinical course.

Fig. 5.
Fig. 5.

Hypothetical algorithm of the pathogenesis of dural arteriovenous malformations (DAVMs). An obstruction to venous outflow, such as a sinus thrombus, would produce venous hypertension in some patients. Venous hypertension reduces (thin downward facing arrow) cerebral perfusion and produces venous ischemia. Tissue hypoxia stimulates angiogenesis in an attempt to reverse ischemia (negative feedback inhibition [minus sign]). Aberrant angiogenic activity by dural blood vessels would lead to arteriovenous shunting into the dural sinuses and to DAVM formation. Arterialization of venous sinuses exacerbates venous hypertension (by increasing arterial inflow) and outflow occlusion (by promoting thrombus propagation), thereby creating a vicious circle that would enlarge the DAVM, cause retrograde cortical venous drainage, and lead to a malignant clinical course. In contrast to this pathophysiology, physiological angiogenesis attempts to increase blood supply to ischemic tissues and to establish collateral venous drainage around an obstructed sinus to relieve venous hypertension. The DAVMs not exposed to venous hypertension would have a benign clinical course or would regress.

Venous Hypertension and Initiation of Dural AVMs

Experimental data collected from rat models support venous hypertension as the primary event in the pathogenesis of dural AVMs.5,6,24,64 The CCA—EJV anastomosis results in dural AVM formation, and higher venous pressures, produced by obstructing venous outflow, further increase these rates.24,64 In the clinical arena, the venous hypertension associated with dural AVM formation appears to be related more to obstruction of venous outflow than to arteriovenous shunting. According to Poiseuille's law, doubling blood flow through an arteriovenous fistula increases sinus pressure 16-fold. Thus, a change in venous outflow is likely to produce a greater effect on sinus pressure than a similar change in blood flow, a prediction that has been confirmed in animal models.6

One mechanism of venous outflow obstruction is sinus thrombosis, which occurs as a result of trauma, surgery, infection, and spontaneous causes.4,8,24,26,39,51 Houser, et al.,26 identified sinus thrombosis as an initiating event in the pathogenesis of dural AVMs after observing thrombosed sinuses in 80% of patients with dural AVMs and after demonstrating their formation angiographically in two of these patients. However, most normal individuals will tolerate outflow occlusion without developing venous hypertension.31 In our experience with surgical occlusion of the sigmoid sinus during the combined supra- and infratentorial approach,58 we have never observed significant elevations (> 10 mm Hg) in venous pressure. Apparently, sinus thrombosis causes venous hypertension when outflow is significantly compromised and collateral venous drainage is inadequate. Only a small subset of patients with outflow occlusion is susceptible to venous hypertension and dural AVM formation.

Venous Ischemia and Angiogenesis

The presence of hypoxia as a result of venous hypertension was not directly measured in these experiments. Although measures of oxygen tension in the cerebrum or venous blood might have been conclusive, Herman and colleagues24 documented histologically diffuse cortical ischemia in 19 of 20 rats using this same model. It is well recognized that venous hypertension causes passive congestion and decreases cerebral perfusion.26,27,29,34,38,53,54,62,66 In addition, the sacrifice of one carotid artery for the anastomosis probably contributed to cerebral ischemia. Ischemia may therefore be involved in this experimental model.

In an angiogenic hypothesis for dural AVM formation, the ischemia induced by venous hypertension would elicit angiogenesis. Expression of angiogenic stimulators and angiogenic activity are induced by tissue hypoxia,16,18,20,28,35,36,40,42,45,60 and vascular endothelial growth factor is an example of such a stimulator.1,9,10,23,25,28,30,35,36,41,42,45,46,48,50,52,56,57,60 Ischemic cells secrete diffusible angiogenic factors that stimulate endothelial cell proliferation and migration.11,16–18,33,40 Humoral factors released by the ischemic brain adjacent to the dural sinuses could affect meningeal capillaries, which could form endothelial sprouts, develop lumina, and connect to dural sinuses to initiate arteriovenous shunting.

In earlier angiogenic hypotheses about dural AVM formation,7,8,24,26,62 inflammation was proposed as the putative trigger. Houser, et al.,26 for example, suggested that inflammation associated with the organization of a sinus thrombosis and the process of recanalization—rather than cerebral ischemia—stimulated angiogenic activity. Sundt and Piepgras62 proposed that this inflammatory angiogenesis produced vascular connections between the dura mater and the patent portion of the sinus to form dural AVMs. Inflammatory angiogenesis, however, fails to explain why some dural AVMs form in locations remote from the thrombosis and has now been refuted experimentally. In a rat model,24 control animals with sinus thrombosis and venous outflow occlusion failed to develop dural AVMs, indicating that thrombus organization by itself was insufficient to promote their formation. The current study replicated this finding. Ischemia induced by venous hypertension, rather than inflammation induced by thrombus recanalization, would appear to be the critical initiator of dural AVM formation.

Other pathogenesis hypotheses implicate ischemia only indirectly. Terada and associates64 proposed that chronic exposure to venous hypertension would cause dural arterioles to dilate and lose sphincter control, thereby causing dysautoregulatory vasodilation.43,59,61 These dysautoregulated vessels would then act like arteriovenous shunts and form dural AVMs. Therefore, the proposed ischemic effects of venous hypertension are unique to the current hypothesis regarding angiogenesis.

Hemodynamic Amplification of Dural AVM Formation

In the angiogenesis hypothesis, arteriovenous shunting results from newly formed connections between dural arterioles and sinuses. Arterial blood flow into the sinuses would exacerbate the underlying venous hypertension and turbulent blood flow would exacerbate the underlying venous outflow occlusion. Histopathological studies of dural AVMs have demonstrated that turbulent arterial blood flow into venous sinuses causes intimal injury, thickening of the sinus wall, and development of lumenal thrombosis, all of which further restrict venous outflow and increase sinus pressures.5,49 Therefore, arterialization of the sinuses would amplify both the venous hypertension and the outflow occlusion that underlie dural AVM formation. A vicious circle would be initiated that would promote continued angiogenic activity and enlarge the dural AVM.

Other hypotheses fail to account for the onset of arteriovenous shunting. Several hypotheses have indicated that dural AVMs simply arise from preexisting embryonic arteriovenous communications in normal dura mater32,55 that open to create abnormal fistulas between meningeal arteries and dural sinuses.2,4,13 Why these vestigial channels open is unexplained, however, and venous hypertension is not involved in the pathogenesis.

The clinical course of patients with dural AVMs appears to depend on how thrombus remodels and redirects blood flow in the sinuses. Hence, dural AVMs have been classified according to their drainage pattern into sinuses and cortical veins.7,12,13 These classification systems are heuristic because they predict clinical course, but they reveal nothing about pathogenesis except this final step. Sinus thrombosis that traps a segment of the sinus may force retrograde venous drainage through cortical veins, predisposing patients to a more aggressive neurological course.3,7,13,26,38,44

Implications for Treatment

Any hypothesis of dural AVM formation must explain the regression observed in this study after normal venous pressures were restored. Spontaneous cures are usually attributed to thrombosis of the nidus,38 but there was no apparent cause for thrombosis in these experiments. According to the angiogenesis hypothesis, eliminating venous hypertension would normalize cerebral perfusion and turn off the ischemic stimulus for angiogenic activity. Therefore, occlusion of the CCA—EJV anastomosis in the rat model may act as negative feedback inhibition of angiogenesis. Under normal circumstances, angiogenesis is strictly controlled, and negative regulators defend vascular endothelium from stimulation.14,16 In the absence of angiogenic stimulation, these negative regulators might cause dural AVMs to regress, much like antiangiogenic agents (for instance, interferon α-2a) cause hemangiomas to regress.17,65

Angiogenesis in response to venous hypertension might serve to reverse venous ischemia. Neovascularization might directly increase blood supply to ischemic tissues or establish collateral venous drainage around a thrombosed sinus. In either case, angiogenesis could relieve the pathophysiology that stimulated it and reverse the progression of disease. The development of a dural AVM would therefore represent an aberration of physiological angiogenesis. Like diabetic retinopathy and capillary hemangiomas, dural AVMs might be another example of an angiogenic disease.15

Acknowledgments

We gratefully acknowledge Adrienne C. Scheck, Ph.D., for reviewing the manuscript, John Pemberton and Conrad Ballecer for their technical support, Robert Amos for filming angiograms, Stacy Ruzicka for photographic assistance, Shelley A. Kick, Ph.D., Senior Editor, for her editorial expertise, and the Neuroscience Publications Office for editorial assistance.

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    Ikeda EAchen MGBreier Get al: Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem 270:19761197661995J Biol Chem 270:

  • 29.

    Ito MSonokawa TMishina Het al: Reversible dural arteriovenous malformation-induced venous ischemia as a cause of dementia: treatment by surgical occlusion of draining dural sinus: case report. Neurosurgery 37:118711921995Neurosurgery 37:

  • 30.

    Jakeman LBWiner JBennett GLet al: Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J Clin Invest 89:2442531992J Clin Invest 89:

  • 31.

    Kalbag RMWoolf AL: London: Oxford University Press1967

  • 32.

    Kerber CWNewton TH: The macro and microvasculature of the dura mater. Neuroradiology 6:1751791973Neuroradiology 6:

  • 33.

    Klagsbrun MD'Amore PA: Regulators of angiogenesis. Annu Rev Physiol 53:2172391991Annu Rev Physiol 53:

  • 34.

    Kurata AMiyasaka YYoshida Tet al: Venous ischemia caused by dural arteriovenous malformation. Case report. J Neurosurg 80:5525551994J Neurosurg 80:

  • 35.

    Ladoux AFrelin C: Expression of vascular endothelial growth factor by cultured endothelial cells from brain microvessels. Biochem Biophys Res Commun 194:7998031993Biochem Biophys Res Commun 194:

  • 36.

    Ladoux AFrelin C: Hypoxia is a strong inducer of vascular endothelial growth factor mRNA expression in the heart. Biochem Biophys Res Commun 195:100510101993Biochem Biophys Res Commun 195:

  • 37.

    Lasjaunias PBerenstein A: Surgical Neuroangiography. Vol 2: Endovascular Treatment of Craniofacial Lesions. Berlin: Springer-Verlag1987273315Surgical Neuroangiography. Vol 2: Endovascular Treatment of Craniofacial Lesions.

  • 38.

    Lasjaunias PChiu MTer Brugge Ket al: Neurological manifestations of intracranial dural arteriovenous malformations. J Neurosurg 64:7247301986J Neurosurg 64:

  • 39.

    Lasjaunias PLopez-Ibor LAbanou Aet al: Radiological anatomy of the vascularization of cranial dural arteriovenous malformations. Anat Clin 6:87991984Anat Clin 6:

  • 40.

    Lawton MTShetter AGShapiro Wet al: Angiogenesis factors and their clinical applications. BNI Quarterly 9:46541993BNI Quarterly 9:

  • 41.

    Leung DWCachianes GKuang WJet al: Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:130613121989Science 246:

  • 42.

    Levy APLevy NSWegner Set al: Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem 270:13333133401995J Biol Chem 270:

  • 43.

    MacKenzie ETStrandgaard SGraham DIet al: Effects of acutely induced hypertension in cats on pial arteriolar caliber, local cerebral blood flow, and the blood-brain barrier. Circ Res 39:33411976Circ Res 39:

  • 44.

    Malik GMPearce JEAusman JIet al: Dural arteriovenous malformations and intracranial hemorrhage. Neurosurgery 15:3323391984Neurosurgery 15:

  • 45.

    Minchenko ABauer TSalceda Set al: Hypoxic stimulation of vascular endothelial growth factor expression in vitro and in vivo. Lab Invest 71:3743791994in vitro and in vivo. Lab Invest 71:

  • 46.

    Monacci WTMerrill MJOldfield EH: Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. Am J Physiol 264:C995C10021993Am J Physiol 264:

  • 47.

    Morcos JJHeros RC: Supratentorial arteriovenous malformationsCarter LPSpetzler RFHamilton MG (eds): Neurovascular Surgery. New York: McGraw-Hill19959791004Neurovascular Surgery.

  • 48.

    Namiki ABrogi EKearney Met al: Hypoxia induces vascular endothelial growth factor in cultured human endothelial cells. J Biol Chem 270:31189311951995J Biol Chem 270:

  • 49.

    Nishijima MTakaku AEndo Set al: Etiological evaluation of dural arteriovenous malformations of the lateral and sigmoid sinuses based on histopathological examinations. J Neurosurg 76:6006061992J Neurosurg 76:

  • 50.

    Nomura MYamagishi SHarada Set al: Possible participation of autocrine and paracrine vascular endothelial growth factors in hypoxia-induced proliferation of endothelial cells and pericytes. J Biol Chem 270:28316283241995J Biol Chem 270:

  • 51.

    Piton JGuilleux MHGuibert-Tranier Fet al: Fistulae of the lateral sinus. J Neuroradiol 11:1431591984J Neuroradiol 11:

  • 52.

    Plate KHBreier GMillauer Bet al: Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res 53:582258271993Cancer Res 53:

  • 53.

    Rekate HL: Circuit diagram of the circulation of cerebrospinal fluid. Pediatr Neurosurg 21:2482531994Rekate HL: Circuit diagram of the circulation of cerebrospinal fluid. Pediatr Neurosurg 21:

  • 54.

    Rekate HLBrodkey JAChizeck HJet al: Ventricular volume regulation: a mathematical model and computer simulation. Pediatr Neurosci 14:77841988Pediatr Neurosci 14:

  • 55.

    Rowbotham GFLittle E: Circulations of the cerebral hemispheres. Br J Surg 52:8211965Br J Surg 52:

  • 56.

    Shweiki DItin ASoffer Det al: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:8438451992Nature 359:

  • 57.

    Shweiki DNeeman MItin Aet al: Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis. Proc Natl Acad Sci USA 92:7687721995Proc Natl Acad Sci USA 92:

  • 58.

    Spetzler RFDaspit CPPappas CTE: The combined supra- and infratentorial approach for lesions of the petrous and clival regions: experience with 46 cases. J Neurosurg 76:5885991992J Neurosurg 76:

  • 59.

    Spetzler RFWilson CBWeinstein Pet al: Normal perfusion pressure breakthrough theory. Clin Neurosurg 25:6516721978Clin Neurosurg 25:

  • 60.

    Stein INeeman MShweiki Det al: Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes. Mol Cell Biol 15:536353681995Mol Cell Biol 15:

  • 61.

    Strandgaard SOlesen JSkinhøj Eet al: Autoregulation in brain circulation in severe arterial hypertension. Br Med J 1:5075101973Br Med J 1:

  • 62.

    Sundt TM JrPiepgras DG: The surgical approach to arteriovenous malformations of the lateral and sigmoid dural sinuses. J Neurosurg 59:32391983J Neurosurg 59:

  • 63.

    Tamargo RJBok RABrem H: Angiogenesis inhibition by minocycline. Cancer Res 51:6726751991Cancer Res 51:

  • 64.

    Terada THigashida RTHalbach VVet al: Development of acquired arteriovenous fistulas in rats due to venous hypertension. J Neurosurg 80:8848891994J Neurosurg 80:

  • 65.

    White CWSondheimer HMCrouch ECet al: Treatment of pulmonary hemangiomatosis with recombinant interferon ALFA-2a. N Engl J Med 320:119712001989N Engl J Med 320:

  • 66.

    Willinsky RTerbrugge KLasjaunias Pet al: The variable presentations of craniocervical and cervical dural arteriovenous malformations. Surg Neurol 34:1181231990Surg Neurol 34:

Dr. Lawton is recipient of the 1997 World Federation of Neurosurgical Societies Young Neurosurgeon Award, presented at the 11th International Congress of Neurological Surgeons, July 6–11, 1997, Amsterdam, The Netherlands.

Article Information

Address reprint requests to: Robert F. Spetzler, M.D., Neuroscience Publications, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, Arizona 85013–4496. email: neuropub@mha.chw.edu.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Illustrations showing the surgical procedures that induced (left) or did not induce (right) venous hypertension in rats.

  • View in gallery

    Photographs showing angiogenic activity of rat dura mater assayed in the rabbit cornea. Blood vessels grow from the cornea—sclera junction toward the implant in the corneal pocket. Upper Left: No vessels (angiogenesis index of 0). Upper Right: One to 10 vessels (angiogenesis index of 1). Lower Left: More than 10 vessels, loosely packed with the iris visible through gaps between the vessels (angiogenesis index of 2). Lower Right: More than 10 vessels, tightly packed with no gaps between the vessels (angiogenesis index of 3). Original magnification × 10.

  • View in gallery

    Bar graph displaying angiogenic activity (average angiogenesis index) of dura sampled from rats with and without venous hypertension at 1, 2, and 3 weeks. Error bars depict the standard error of the mean.

  • View in gallery

    Cerebral angiograms demonstrating the four angiographic grades. A and B: Anteroposterior (AP [A]) and lateral (B) angiograms obtained in nonhypertensive rat showing arterial anatomy (Grade 0). C: Lateral angiogram showing a facial AVM (arrowhead) located in the nose with a prominent early draining vein (arrow) (Grade I). D: An AP angiogram showing a dural AVM (arrowhead) and an abnormal early draining vein (arrow), anterior to the SS thrombosis, as it drains laterally into the inferior cerebral sinus and posterior facial vein; no facial AVM is seen (Grade II). E and F: An AP (E) and lateral (F) angiogram showing a facial and dural AVM (Grade III, arrowheads) and their associated draining veins (arrows).

  • View in gallery

    Hypothetical algorithm of the pathogenesis of dural arteriovenous malformations (DAVMs). An obstruction to venous outflow, such as a sinus thrombus, would produce venous hypertension in some patients. Venous hypertension reduces (thin downward facing arrow) cerebral perfusion and produces venous ischemia. Tissue hypoxia stimulates angiogenesis in an attempt to reverse ischemia (negative feedback inhibition [minus sign]). Aberrant angiogenic activity by dural blood vessels would lead to arteriovenous shunting into the dural sinuses and to DAVM formation. Arterialization of venous sinuses exacerbates venous hypertension (by increasing arterial inflow) and outflow occlusion (by promoting thrombus propagation), thereby creating a vicious circle that would enlarge the DAVM, cause retrograde cortical venous drainage, and lead to a malignant clinical course. In contrast to this pathophysiology, physiological angiogenesis attempts to increase blood supply to ischemic tissues and to establish collateral venous drainage around an obstructed sinus to relieve venous hypertension. The DAVMs not exposed to venous hypertension would have a benign clinical course or would regress.

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Ladoux AFrelin C: Hypoxia is a strong inducer of vascular endothelial growth factor mRNA expression in the heart. Biochem Biophys Res Commun 195:100510101993Biochem Biophys Res Commun 195:

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40.

Lawton MTShetter AGShapiro Wet al: Angiogenesis factors and their clinical applications. BNI Quarterly 9:46541993BNI Quarterly 9:

41.

Leung DWCachianes GKuang WJet al: Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:130613121989Science 246:

42.

Levy APLevy NSWegner Set al: Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem 270:13333133401995J Biol Chem 270:

43.

MacKenzie ETStrandgaard SGraham DIet al: Effects of acutely induced hypertension in cats on pial arteriolar caliber, local cerebral blood flow, and the blood-brain barrier. Circ Res 39:33411976Circ Res 39:

44.

Malik GMPearce JEAusman JIet al: Dural arteriovenous malformations and intracranial hemorrhage. Neurosurgery 15:3323391984Neurosurgery 15:

45.

Minchenko ABauer TSalceda Set al: Hypoxic stimulation of vascular endothelial growth factor expression in vitro and in vivo. Lab Invest 71:3743791994in vitro and in vivo. Lab Invest 71:

46.

Monacci WTMerrill MJOldfield EH: Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. Am J Physiol 264:C995C10021993Am J Physiol 264:

47.

Morcos JJHeros RC: Supratentorial arteriovenous malformationsCarter LPSpetzler RFHamilton MG (eds): Neurovascular Surgery. New York: McGraw-Hill19959791004Neurovascular Surgery.

48.

Namiki ABrogi EKearney Met al: Hypoxia induces vascular endothelial growth factor in cultured human endothelial cells. J Biol Chem 270:31189311951995J Biol Chem 270:

49.

Nishijima MTakaku AEndo Set al: Etiological evaluation of dural arteriovenous malformations of the lateral and sigmoid sinuses based on histopathological examinations. J Neurosurg 76:6006061992J Neurosurg 76:

50.

Nomura MYamagishi SHarada Set al: Possible participation of autocrine and paracrine vascular endothelial growth factors in hypoxia-induced proliferation of endothelial cells and pericytes. J Biol Chem 270:28316283241995J Biol Chem 270:

51.

Piton JGuilleux MHGuibert-Tranier Fet al: Fistulae of the lateral sinus. J Neuroradiol 11:1431591984J Neuroradiol 11:

52.

Plate KHBreier GMillauer Bet al: Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res 53:582258271993Cancer Res 53:

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55.

Rowbotham GFLittle E: Circulations of the cerebral hemispheres. Br J Surg 52:8211965Br J Surg 52:

56.

Shweiki DItin ASoffer Det al: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:8438451992Nature 359:

57.

Shweiki DNeeman MItin Aet al: Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis. Proc Natl Acad Sci USA 92:7687721995Proc Natl Acad Sci USA 92:

58.

Spetzler RFDaspit CPPappas CTE: The combined supra- and infratentorial approach for lesions of the petrous and clival regions: experience with 46 cases. J Neurosurg 76:5885991992J Neurosurg 76:

59.

Spetzler RFWilson CBWeinstein Pet al: Normal perfusion pressure breakthrough theory. Clin Neurosurg 25:6516721978Clin Neurosurg 25:

60.

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62.

Sundt TM JrPiepgras DG: The surgical approach to arteriovenous malformations of the lateral and sigmoid dural sinuses. J Neurosurg 59:32391983J Neurosurg 59:

63.

Tamargo RJBok RABrem H: Angiogenesis inhibition by minocycline. Cancer Res 51:6726751991Cancer Res 51:

64.

Terada THigashida RTHalbach VVet al: Development of acquired arteriovenous fistulas in rats due to venous hypertension. J Neurosurg 80:8848891994J Neurosurg 80:

65.

White CWSondheimer HMCrouch ECet al: Treatment of pulmonary hemangiomatosis with recombinant interferon ALFA-2a. N Engl J Med 320:119712001989N Engl J Med 320:

66.

Willinsky RTerbrugge KLasjaunias Pet al: The variable presentations of craniocervical and cervical dural arteriovenous malformations. Surg Neurol 34:1181231990Surg Neurol 34:

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