The relationship between venous hypertension and expression of vascular endothelial growth factor: hemodynamic and immunohistochemical examinations in a rat venous hypertension model

doi:10.1016/j.surneu.2006.10.075

Surgical Neurology

Volume 68, Issue 3, September 2007, Pages 277-284

https://doi.org/10.1016/j.surneu.2006.10.075 Get rights and content

Abstract

Background

Venous hypertension is regarded as an important factor in the pathogenesis of dural arteriovenous fistula (DAVF). We investigate histologic reaction of dural sinus under the condition of venous hypertension using a rat venous hypertension model to present hemodynamic and immunohistochemical effect in the development of DAVF.

Methods

Twenty-four Sprague-Dawley male rats were divided into venous hypertension and control groups. Venous hypertension was induced with a left common carotid artery–external jugular vein anastomosis and an occlusion of a right posterior facial vein. Measurements of systemic mean arterial pressure, draining vein pressure (DVP), and cerebral perfusion pressure (CPP) were conducted on the next day, at 7 days, and at 28 days after surgery, and the rats were killed for histologic examinations.

Results

Postoperative DVP increased significantly in venous hypertension group compared to control group (35 ± 5 vs 13 ± 2 mm Hg, P < .05). Increased DVP remained above 30 mm Hg throughout the observation period. Postoperative CPP decreased significantly in venous hypertension group compared to control group (49 ± 8 vs 86 ± 9 mm Hg, P < .05). In venous hypertension group, there was a significant difference between days 1 and 28 (49 ± 8 vs 64 ± 8 mm Hg, P < .05). Histologic examination revealed thickening of connective tissues, proliferation of fibroblasts, and strong expression of vascular endothelial growth factor (VEGF) in endothelium under venous hypertension condition. Immunostained VEGF cells decreased significantly from day 7 to day 28 (100 ± 16 vs 72 ± 19 cells, P < .05). A positive correlation was observed between DVP and VEGF expression (Pearson correlation coefficient; r = 0.671, P = .0017). There was a negative correlation between CPP and immunostained VEGF cells (r = −0.702, P = .0089).

Conclusions

These results suggest that venous hypertension is associated with increased expression of VEGF, and a decreased CPP may have a potential effect in VEGF expression under venous hypertension condition. These factors are speculated to play an important role in progression of DAVF.

Introduction

The pathogenesis of dural arteriovenous fistula (DAVF) has been of great interest and has given rise to many theories. Previous studies have generally considered DAVF to be acquired lesions, and etiologic factors such as neurosurgical procedures [20], [25], [32], [35], [37] and cranial trauma [3], [15], [22], [23] have been reported. These factors may be associated with sinus occlusion and venous hypertension, inducing the formation of DAVF [1], [3], [6], [9], [13], [17], [21]. Recently, although the expression of angiogenic factors has been identified in DAVF [30], [34], their mechanisms remain unclear. Since DAVF is usually diagnosed after clinical presentation, it is difficult to determine its origin and development. To clarify this issue, a rat arteriovenous fistula model was created to investigate the contribution of sinus occlusion and venous hypertension to the formation of DAVF [2]. Several studies have demonstrated the formation of DAVF using morphologic methods [11], [19], [29], [38]. Furthermore, the expression of angiogenic factors has been established in the lesion [8], [19], [24], [27]. In the present study, we investigate histologic reaction of dural sinus under the condition of venous hypertension using a rat venous hypertension model to present hemodynamic and immunohistochemical effect in the development of DAVF.

Section snippets

Methods

This study was approved by the Animal Care and Use Committee of the Nagoya University, Nagoya, Japan. The care and handling of the animals were performed in accordance with National Institutes of Health guidelines for the care and handling of animals. Twenty-four Sprague-Dawley rats weighing between 260 and 400 g were used in this study. Animals were housed under standard laboratory conditions and maintained on standard laboratory chow and water. To exclude any hormonal effects on DAVF

Results

No rats died during this study. The left common carotid artery–external jugular vein anastomosis was confirmed patent in all venous hypertension group rats (n = 12) on day 1. The diameters of both the left distal external jugular vein and the right external jugular vein were dramatically dilated with pulsation.

Rat venous hypertension model

A rat DAVF model was created to clarify the contribution of venous hypertension and venous outflow obstruction to the formation of DAVF [2]. The model was surgically created by common carotid artery–external jugular vein anastomosis and the contralateral draining vein occlusion. Hemodynamic [2], [7], [11], [19], [36], [38], angiographic [11], [19], [27], [29], and histologic [11], [24], [27], [29], [38] investigations were performed using this model.

In previous reports, sinus hypertension was

Conclusion

Although the pathogenesis of DAVF is complex, venous hypertension is associated with increased expression of VEGF. Under venous hypertension condition, a decreased CPP may have a potential effect in VEGF expression. These factors are speculated to play an important role in progression of DAVF. For further investigations, it may be interesting to study other immunohistochemical factors such as hypoxia inducible factor 1α for evaluating tissue hypoxia and Ki-67 for endothelium proliferation [31].

Acknowledgment

The authors thank Tetsuro Nagasaka, MD (Department of Laboratory Medicine, Nagoya University Graduate School of Medicine), for suggestions with histologic analyses.

References (38)

R.A. Roski et al.
Middle meningeal artery trauma
Surg Neurol
(1982)
W. Tirakotai et al.
Immunohistochemical study in dural arteriovenous fistulas and possible role of local hypoxia for the de novo formation of dural arteriovenous fistulas
Clin Neurol Neurosurg
(2005)
R. Yassari et al.
Dural arteriovenous fistula after craniotomy for pilocytic astrocytoma in a patient with protein S deficiency
Surg Neurol
(2002)
I.A. Awad et al.
Intracranial dural arteriovenous malformations: factors predisposing to an aggressive neurological course
J Neurosurg
(1990)
J.B. Bederson et al.
Intracranial venous hypertension and the effects of venous outflow obstruction in a rat model of arteriovenous fistula
Neurosurgery
(1991)
M.Y. Chaudhary et al.
Dural arteriovenous malformation of the major venous sinuses: an acquired lesion
AJNR Am J Neuroradiol
(1982)
N. Ferrara et al.
The vascular endothelial growth factor family of polypeptides
J Cell Biochem
(1991)
J. Folkman et al.
Angiogenic factors
Science
(1987)
D.A. Graeb et al.
Radiological and pathological aspects of dural arteriovenous fistulas. Case report
J Neurosurg
(1986)
J. Hai et al.
A new rat model of chronic cerebral hypoperfusion associated with arteriovenous malformations
J Neurosurg
(2002)

J. Hai et al.

Vascular endothelial growth factor expression and angiogenesis induced by chronic cerebral hypoperfusion in rat brain

Neurosurgery

(2003)

Y. Hamada et al.

Histopathological aspects of dural arteriovenous fistulas in the transverse-sigmoid sinus region in nine patients

Neurosurgery

(1997)

T. Hashimoto et al.

Abnormal pattern of Tie-2 and vascular endothelial growth factor receptor expression in human cerebral arteriovenous malformations

Neurosurgery

(2000)

J.M. Herman et al.

Genesis of a dural arteriovenous malformation in a rat model

J Neurosurg

(1995)

P. Hofman et al.

Endothelial cell hypertrophy induced by vascular endothelial growth factor in the retina: new insights into the pathogenesis of capillary nonperfusion

Arch Ophthalmol

(2001)

O.W. Houser et al.

Arteriovenous malformation affecting the transverse dural venous sinus—an acquired lesion

Mayo Clin Proc

(1979)

M. Ide et al.

Tumor cell counting using an image analysis program for MIB-1 immunohistochemistry

Neurol Med Chir

(1997)

T. Ishikawa et al.

Development of anterior cranial fossa dural arteriovenous malformation following head trauma. Case report

J Neurosurg

(1997)

R. Kimura et al.

Vascular endothelial growth factor antagonist reduces brain edema formation and venous infarction

Stroke

(2005)

Cited by (68)

Cerebral venous disorders: Diagnosis and endovascular management
2023, Journal of Neuroradiology
The role of the venous circulation in neurological diseases has been underestimated. In this review, we present an overview of the intracranial venous anatomy, venous disorders of the central nervous system, and options for endovascular management. We discuss the role the venous circulation plays in various neurological diseases including cerebrospinal fluid (CSF) disorders (intracranial hypertension and intracranial hypotension), arteriovenous diseases, and pulsatile tinnitus. We also shed light on emergent cerebral venous interventions including transvenous brain-computer interface implantation, transvenous treatment of communicating hydrocephalus, and the endovascular treatment of CSF-venous disorders.
State of the Art and Future Direction in Diagnosis, Molecular Biology, Genetics, and Treatment of Brain Arteriovenous Malformations
2022, World Neurosurgery
Citation Excerpt :
Another possible origin could be intracranial venous hypertension,72 because it is closely associated with the upregulation of VEGF and HIF-1.73 Kojima et al.50 induced intracranial venous hypertension in rats for a week. These investigators examined the brain tissue looking for VEGF and observed that it was strongly expressed in the endothelium of vessels.
Brain arteriovenous malformations (bAVMs) are uncommon and represent a heterogeneous group of lesions. Although these 2 facts have delayed research on this topic, knowledge about the pathophysiology, diagnosis, and treatment of bAVMs has evolved in recent years.
We conducted a review of the literature to update the knowledge about diagnosis, molecular biology, genetic, pathology, and treatment by searching for the following terms: “Epidemiology AND Natural History,” “risk of hemorrhage,” “intracranial hemorrhage,” “diagnosis,” “angiogenesis,” “molecular genetics,” “VEGF,” “KRAS,” “radiosurgery,” “endovascular,” “microsurgery,” or “surgical resection.”
Our understanding of bAVMs has significantly evolved in recent years. The latest investigations have helped in defining some molecular pathways involved in the pathology of bAVM. Although there is still more to learn and discover, describing these pathways will allow the creation of targeted treatments that could improve the prognosis of patients with bAVMs.
Superficial middle temporal vein as a pivotal route to embolize dural carotid–cavernous fistulas
2021, Journal of Clinical Neuroscience
Dural carotid–cavernous fistulas (DCCF) are located in the cavernous sinus wall involving the arterial feeders from the external and internal carotid arteries. The venous route usually passes through the internal jugular vein and inferior petrosal sinus (IPS) up to the pathologic shunts of the cavernous sinus. In cases of a thrombosed IPS, catheterization is not always possible because of the obstruction. Here, we report eight cases of DCCF treated with endovascular transvenous embolization via the superficial middle temporal vein (SMTV). A retrospective study involving eight patients with DCCF treated with transvenous embolization via SMTV was performed. In six patients, IPS was thrombosed. In one patient, IPS was patent, but we could not catheterize the internal jugular vein. In the other patient, because of the compartmentalization of the cavernous sinus, we could not access the anterior part of the cavernous sinus via IPS. Therefore, we performed the embolization via SMTV to occlude the shunts of the anterior part of the cavernous sinus.
In all eight cases, navigating through the tortuous junction of the angular vein and superior ophthalmic vein (SOV) was possible. After transvenous catheterization of the cavernous sinus via SMTV, placement of coils resulted in complete occlusion of DCCF with clinical improvement in all eight patients. In the endovascular treatment of DCCF, the transfemoral approach via SMTV provides a pivotal route alternative to other transvenous routes. In patients with dilated SOV, catheterization of the cavernous sinus via SMTV is usually successful.
Efficiency of Endovascular Therapy for Bilateral Cavernous Sinus Dural Arteriovenous Fistula
2021, World Neurosurgery
Citation Excerpt :
It was hypothesized that the pathogenesis of bilateral CS-dAVFs possibly developed simultaneously or subsequently from the first fistula as a result of the same trauma or unknown cause. The major precipitation from venous thrombosis and venous hypertension is neoangiogenesis.12,13 Venous hypertension can affect the contralateral CS via the ICS, which then enhances the occlusion events of the IPS.
The principles of endovascular treatment of bilateral cavernous sinus dural arteriovenous fistula (CS-dAVF) are not well established because of the complexity in the number of fistula tracts and their behavior, which seems to be more aggressive. We aimed to determine an efficient technique for endovascular treatment of bilateral CS-dAVF and the associated factors to achieve good clinical and angiographic outcomes.
The data were analyzed from 165 consecutive patients diagnosed with CS-dAVF from January 2005 to September 2018. The demographic data included approaching route, embolization times, embolization material, sequence of embolization, number of embolization sessions, and angiographic and clinical outcomes. Interrater agreement of bilateral CS-dAVF diagnosis was performed using the κ coefficient. The factors associated with treatment outcome were analyzed using a Pearson χ² test.
Bilateral CS-dAVF was detected in 43 patients (26%). Angiographic presentations that showed evidence of sinus thrombosis, dangerous venous drainage, and higher Satomi classification were more commonly found in bilateral CS-dAVF than in unilateral CS-dAVF. Good clinical outcome and cure from angiography were obtained in 90% and 74%, respectively. Ipsilateral inferior petrosal sinus–intercavernous sinus–contralateral cavernous sinus catheterization was the major approach route of treatment. The factors associated with improved clinical outcome were transvenous approach, shunt closure, coil embolization, and sequencing the embolization (P < 0.001).
Dangerous venous drainage tends to increase in bilateral CS-dAVF. Retrograde ipsilateral inferior petrosal sinus catheterization using coil embolization and sequencing the embolization are the major concerns for treatment.
Primary conus medullaris arteriovenous shunt and secondary lumbo-sacral epidural arteriovenous fistula: One malformation can hide another
2021, Journal of Neuroradiology
We report an anatomical-based association between conus medullaris pial arteriovenous shunt that drain caudally towards the lumbosacral area with very delayed onset of an acquired lumbar epidural shunt, draining secondarily towards intradural veins and responsible for a venous congestive myelopathy with identical clinical symptoms. These patients require close clinical and imaging follow-ups in order to propose adequate treatments before onset of irreversible neurological deficits. MRA should include the lumbo-sacral area in its field of view.
Development of a murine iliac arteriovenous fistula model for examination of hemodialysis access-related limb pathophysiology
2021, JVS-Vascular Science
Hemodialysis access-related hand dysfunction is a common clinical feature of patients with chronic kidney disease (CKD) after arteriovenous fistula (AVF) placement. The heterogeneity in symptoms and the lack of a predictive association with changes in hemodynamic alterations precipitated by the AVF suggest that other factors are involved in the mechanisms responsible for causing hand and limb dysfunction postoperatively. To the best of our knowledge, no suitable animal models have provided a platform for performing preclinical experiments designed to elucidate the biologic drivers of access-related hand dysfunction. Therefore, our objective was to develop a novel murine AVF model that could be used to study dialysis access-related limb dysfunction.
Male 8-week-old C57BL/6J mice (n = 15/group) were exposed to either an adenine-supplemented diet to induce CKD or casein-based chow (control). Four weeks after the diet intervention, the mice were randomly assigned to receive an iliac AVF (n = 10/group) or sham surgery (n = 5/group) on the left hindlimb. The mice were sacrificed 2 weeks after surgery, and AVF specimens and hindlimb skeletal muscles were collected for further analysis.
Before AVF or sham surgery, the glomerular filtration rates were significantly reduced and the blood urea nitrogen levels were significantly elevated in the CKD groups compared with the controls (P < .05). AVF surgery was associated with an ∼80% patency rate among the survivors (four control and three CKD mice died postoperatively). Patency was verified by changes in hemodynamics using Doppler ultrasound imaging and altered histologic morphology. Compared with sham surgery, AVF surgery reduced ipsilateral hindlimb perfusion to the tibialis anterior muscle (20%-40%) and paw (40%-50%), which remained stable until euthanasia. Analysis of gastrocnemius muscle mitochondrial respiratory function uncovered a significant decrease (40%-50%) in mitochondrial function in the AVF mice. No changes were found in the muscle mass, myofiber cross-sectional area, or centrally nucleated fiber proportion in the extensor digitorum longus and soleus muscles between the sham and AVF mice.
The results from the present study have demonstrated that iliac AVF formation is a practical animal model that facilitates examination of hemodialysis access-related limb dysfunction. AVF surgery produced the expected hemodynamic changes, and evaluation of the limb muscle revealed a substantial mitochondrial impairment that was present without changes in muscle size.

View all citing articles on Scopus

View full text

GeneticsThe relationship between venous hypertension and expression of vascular endothelial growth factor: hemodynamic and immunohistochemical examinations in a rat venous hypertension model

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Results

Rat venous hypertension model

Conclusion

Acknowledgment

Surg Neurol

Clin Neurol Neurosurg

Surg Neurol

Intracranial dural arteriovenous malformations: factors predisposing to an aggressive neurological course

J Neurosurg

Intracranial venous hypertension and the effects of venous outflow obstruction in a rat model of arteriovenous fistula

Neurosurgery

Dural arteriovenous malformation of the major venous sinuses: an acquired lesion

AJNR Am J Neuroradiol

The vascular endothelial growth factor family of polypeptides

J Cell Biochem

Angiogenic factors

Science

Radiological and pathological aspects of dural arteriovenous fistulas. Case report

J Neurosurg

A new rat model of chronic cerebral hypoperfusion associated with arteriovenous malformations

J Neurosurg

Vascular endothelial growth factor expression and angiogenesis induced by chronic cerebral hypoperfusion in rat brain

Neurosurgery

Histopathological aspects of dural arteriovenous fistulas in the transverse-sigmoid sinus region in nine patients

Neurosurgery

Abnormal pattern of Tie-2 and vascular endothelial growth factor receptor expression in human cerebral arteriovenous malformations

Neurosurgery

Genesis of a dural arteriovenous malformation in a rat model

J Neurosurg

Endothelial cell hypertrophy induced by vascular endothelial growth factor in the retina: new insights into the pathogenesis of capillary nonperfusion

Arch Ophthalmol

Arteriovenous malformation affecting the transverse dural venous sinus—an acquired lesion

Mayo Clin Proc

Tumor cell counting using an image analysis program for MIB-1 immunohistochemistry

Neurol Med Chir

Development of anterior cranial fossa dural arteriovenous malformation following head trauma. Case report

J Neurosurg

Vascular endothelial growth factor antagonist reduces brain edema formation and venous infarction

Stroke

Genetics
The relationship between venous hypertension and expression of vascular endothelial growth factor: hemodynamic and immunohistochemical examinations in a rat venous hypertension model