Development of the Cerebrovasculature and Pathogenesis of Arteriovenous Malformations and Arteriovenous Fistulas

2 Development of the Cerebrovasculature and Pathogenesis of Arteriovenous Malformations and Arteriovenous Fistulas

W. Caleb Rutledge and Tomoki Hashimoto

Abstract

Arteriovenous malformations (AVMs) and arteriovenous fistulas (AVFs) are the most common cerebrovascular malformations (CVMs) and exhibit arteriovenous shunting due to abnormal connections between arteries and veins. Generally, most AVMs and AVFs occur sporadically without a clear genetic basis. Multiple AVMs are often associated with hereditary hemorrhagic telangiectasia and capillary malformation-arteriovenous malformation (CM-AVM) syndrome. The pathogenesis of AVMs and AVFs is not well understood. AVFs are usually acquired from venous hypertension and upregulated angiogenesis, while AVMs are considered congenital malformations, arising from errors during embryogenesis when primitive arteries and veins are in direct communication.

Keywords: vasculogenesis, angiogenesis, arteriovenous malformations (AVMs), arteriovenous fistulas (AVFs)

Key Points

Cerebral vascular malformations are classified functionally by the presence or absence of arteriovenous shunting.
Arteriovenous malformations and arteriovenous fistulas are the most common cerebral vascular malformations.
Arteriovenous malformations and arteriovenous fistulas are high-flow lesions exhibiting arteriovenous shunting.

2.1 Introduction

Arteries are thick-walled vessels capable of withstanding high pressures as they transport blood and nutrients to organs, while veins have thin walls and transmit lower pressures as they carry blood back to the heart. Arteries and veins are never in direct communication, except in the primitive vascular plexus early in embryogenesis when capillary networks organize and mature, ultimately separating arteries from veins. Arteriovenous malformations (AVMs) and arteriovenous fistulas (AVFs) are both characterized by abnormal arteriovenous connections between arteries and veins. Most AVMs occur sporadically without an identifiable genetic basis. However, multiple AVMs often occur as part of syndromes, such as hereditary hemorrhagic telangiectasia (HHT) and capillary malformation-arteriovenous malformation (CM-AVM) syndrome. These disorders provide insight into the pathogenesis of AVMs.

2.2 Development of the Cerebrovasculature

Development of the cerebrovasculature during embryogenesis involves vasculogenesis and angiogenesis.¹ During vasculogenesis, mesoderm-derived angioblasts differentiate into vascular endothelial cells and form capillarylike tubes. This primitive vascular plexus is remodeled into arteries, capillaries, and veins during angiogenesis by vascular endothelial cell proliferation and migration. Cell signaling and growth factors such as Notch pathway signaling and vascular endothelial growth factor (VEGF) are crucial in the development of a functional circulatory system and regulate proliferation and migration of vascular endothelial cells during angiogenesis.

Early in embryonic development, primitive arteries and veins express ephrin-B2 and ephrin-B4, respectively. VEGF, neuropilin-1, and Notch pathway signaling maintain arterial patterning. Activation of VEGF promotes differentiation of the arterial phenotype during embryogenesis through its receptors, VEGFR1 and VEGFR2. Neuropilin-1 is a VEGF co-receptor expressed in arterial endothelial cells and modulates its activity. Activation of VEGF induces Notch signaling. Transcription factors FOXC1 and FOXC2 regulate Notch signaling.² Notch signaling induces ephrin-B2,³ and it also represses ephrin-B4 expression in arterial endothelium and maintains the arterial phenotype.⁴

Similarly, cell signaling and growth factors also regulate development of the venous phenotype; however, venous endothelial cells lack neuropilin-1, and Notch signaling is not activated. The retinoic acid-activated receptor COUP-transcription factor 2 (COUP-TF2) represses Notch signaling and promotes expression of ephrin-B4 to establish the venous phenotype.⁵ Errors during venous and arterial patterning may result in formation of cerebrovascular malformations (CVMs)

2.3 Cerebrovascular Malformations

CVMs are classified functionally by the presence or absence of arteriovenous shunting. AVMs and AVFs shunt blood from the arterial to the venous circulation, while cavernous malformations, telangiectasias, and developmental venous anomalies are nonshunting. Patients commonly present with hemorrhage from rupture, seizures, or focal neurologic deficits from mass effect.

2.4 Arteriovenous Malformations

An AVM is a tangle of abnormal vessels, including a nidus, dilated feeding arteries, and arterialized draining veins without intervening capillaries, and forms a high-flow, low-resistance shunt. AVMs are the most common symptomatic CVM. A hallmark of hemodynamic feature of AVMs is that AVM niduses are exposed to abnormally high blood flow rates. Lacking capillary beds, AVMs act as arteriovenous shunts in the cerebral circulation. High blood flow rates can trigger vascular remodeling, the process that can further affect local hemodynamics. Presence of arteriovenous shunts in peripheral circulation results in venous hypertension in the downstream and arterial hypotension in the upstream. In patients with large, high-flow arteriovenous shunts, there may be normal brain regions in which arterial pressure is below the range of normal autoregulation. Despite significant cerebral arterial hypotension, the majority of patients are free from ischemic symptoms. Hypotensive normal brain regions can, for the most part, be demonstrated to have relatively normal rates of tissue perfusion, implying some adaptive change in total cerebrovascular resistance.⁶^,⁷ Despite their genesis (i.e., acquired or congenital), ongoing vascular remodeling presumably triggered by aberrant local hemodynamic has been considered to be a critical component of their pathophysiology.⁸^,⁹^,¹⁰

Patients commonly present in the third and fourth decade of life with hemorrhage and headaches, seizures, or focal neurologic deficits from mass effect. The overall incidence of AVMs is about 1 per 100,000 person-years. While the annual risk of hemorrhage is about 1% for unruptured AVMs, ruptured AVMs have a much higher rate of rehemorrhage.

Hemodynamic stress can trigger vascular remodeling and angiogenesis by activating endothelial and inflammatory cells. High shear stress—high blood flow—activates endothelial cells and upregulates leukocyte adhesion molecules including intercellular adhesion molecule-1 (ICAM-1) and chemokines such as monocyte chemotactic protein-1 (MCP-1).¹¹^,¹²^,¹³^,¹⁴ These molecules attract circulating neutrophils and monocytes, and facilitate their invasion into the vascular wall. At the same time, shear stress can activate endothelial and smooth muscle cells and promotes their production and release of angiogenic factors and other cytokines that are critical for vascular remodeling.¹⁵^,¹⁶

Along with activated endothelial and smooth muscle cells, these inflammatory cells secrete proteinases, including matrix metalloproteinases (MMPs) and elastases.¹¹ MMPs can destabilize the vascular wall and facilitate vascular remodeling by directly digesting the vascular matrix, activating other proteinases, and releasing angiogenic factors.¹⁷^,¹⁸ Various MMPs and cytokines can interact with each other to carry out physiological and pathological vascular remodeling. Among MMPs, MMP-9 has been most extensively studied, and appears to be critical for various types of vascular remodeling.¹⁷^,¹⁹

There is a growing body of clinical and experimental evidences suggesting that AVMs undergo significant vascular remodeling and angiogenesis in adult life. The variable nature of the clinical course of AVMs, especially with respect to their propensity to growth, regression, and spontaneous hemorrhage, strongly suggests that AVMs represent unstable blood vessels that continuously undergo vascular remodeling. A study that examined interval angiography from a total of 106 patients with mean follow-up periods of 8.4 years showed that over half of the cases increased in size. Approximately one-fifth of the cases decreased in size or vanished,⁸ and this suggests most AVMs undergo active remodeling processes.

Histopathological studies presented further evidence to support the notion of active vascular remodeling and angiogenesis in AVMs. Hatva et al examined the endothelial cell proliferation rates in nine adult AVM specimens using the Ki-67 index and compared them to a single control cortical sample from an 11-year-old patient.²⁰ The Ki-67 index of AVM endothelial cells was higher than the control brain (2.5 vs. 0.5%). A study using a much larger number of specimens (37 AVMs and 5 controls) found approximately a sevenfold increase in nonnesting endothelial cells in AVMs compared to control brain specimens.⁸ This finding provided additional histopathological evidence for the presence of active vascular remodeling and angiogenesis in AVMs.

Underlying mechanisms for active vascular remodeling and angiogenesis in AVMs are under vigorous investigation. A number of angiogenic factors have been implicated in their pathophysiology. Concerted effects of key angiogenic factors may be maintaining active vascular remodeling in AVMs.²¹

MMPs, a family of proteolytic enzymes, degrade extracellular matrix proteins, cell surface molecules, and other pericellular substances.²² By degrading vascular extracellular matrix, MMPs can create a micro-environment that facilitates angiogenesis and vascular remodeling. MMP-9 and MMP-2, having a capability of degrading gelatin, have been extensively studied in physiological and pathological angiogenesis and vascular remodeling. MMP-9, known as gelatinase B, degrades components of vascular extracellular matrices including type IV and V collagen, fibronectin, and elastin.²² High levels of MMP-9 expression are detected in structurally unstable vasculature including cerebral aneurysms,²³^,²⁴ abdominal aortic aneurysms,²⁵^,²⁶^,²⁷ and atherosclerotic carotid artery.²⁸ Excessive degradation of the vascular matrix may contribute to the destabilization of vessels, leading to the weakening of the vessel wall and to vessel rupture.²⁹

An abnormal expression pattern of MMP-9 and TIMPs (tissue inhibitors of metalloproteinases) has been observed in AVMs.³⁰ There is markedly increased MMP-9 activity in AVMs compared with control brain samples. MMP-9 is expressed in the endothelial cell/periendothelial cell layer of AVMs. Along with endothelial and smooth muscle cells, inflammatory cells seem to be a major contributor to the abnormally high levels of MMP-9 in AVM tissue.³¹ The increased MMP-9 activity can be expected to cause degradation of the vascular matrix, impairing structural stability of AVM vessels. Interestingly, higher levels of MMP-9 were associated with clinical characteristics that were linked to AVM hemorrhage.³⁰

There is an increasing interest in utilizing MMP inhibitors to treat vascular diseases including abdominal aortic aneurysms. It has been proposed that pharmacological inhibition of MMPs may stabilize the unstable blood vessels and prevent their rupture.³² In patients with abdominal aortic aneurysm, treatment with doxycycline, a nonspecific MMP inhibitor, for 1 week prior to the repair surgery resulted in decreased MMP-9 and MMP-2 in the wall of the aneurysms.²⁷ Similar results have been reported in patients with atherosclerotic carotid plaques who received doxycycline for 2 to 8 weeks.³³ Doxycycline can inhibit MMP-9 activity in mouse brain, which is hyperstimulated with adenovirally transduced VEGF, an animal model developed in Core C.³⁴ Because MMP-9 appears highly expressed in the nidal vessels, this protease or related ones may serve as potential pharmacological targets to modify clinical behavior of AVMs. A small pilot clinical study demonstrated the feasibility for inhibiting MMP-9 by oral doxycycline in AVM patients.³⁵ Doxycycline or other tetracycline derivatives can be an attracting choice for clinical use because of their long safety record. However, they are not specific inhibitors of MMPs, and they exert cellular effects that are not related to MMP inhibition.

Vascular endothelial cell growth factor-A (VEGF-A) is a potent endothelial cell mitogen and morphogen, which drives vascular remodeling and angiogenesis in a wide variety of tissues and lesions. There are a number of observational studies that showed increased expression of VEGF in AVMs at both protein and mRNA levels.²¹^,³⁶^,³⁷^,³⁸^,³⁹ These reports showed increased VEGF expression in the vascular wall of AVMs, suggesting increased endothelial mitogenic activity in AVMs that can maintain a higher angiogenic activity. Increased expression of VEGF seems to be associated with clinical behavior (i.e., recurrence) of AVMs. Interestingly, a higher degree of astrocytic VEGF expression was associated with recurrence of AVMs after initial resection in small case series.⁴⁰^,⁴¹ Along with other angiogenic factors, abnormally high levels of VEGF may be critical for maintaining active vascular remodeling and angiogenesis in AVMs.