The Role and Therapeutic Implications of Inflammation in the Pathogenesis of Brain Arteriovenous Malformations

Abstract

Brain arteriovenous malformations (bAVMs) are focal vascular lesions composed of abnormal vascular channels without an intervening capillary network. As a result, high-pressure arterial blood shunts directly into the venous outflow system. These high-flow, low-resistance shunts are composed of dilated, tortuous, and fragile vessels, which are prone to rupture. BAVMs are a leading cause of hemorrhagic stroke in children and young adults. Current treatments for bAVMs are limited to surgery, embolization, and radiosurgery, although even these options are not viable for ~20% of AVM patients due to excessive risk. Critically, inflammation has been suggested to contribute to lesion progression. Here we summarize the current literature discussing the role of the immune system in bAVM pathogenesis and lesion progression, as well as the potential for targeting inflammation to prevent bAVM rupture and intracranial hemorrhage. We conclude by proposing that a dysfunctional endothelium, which harbors the somatic mutations that have been shown to give rise to sporadic bAVMs, may drive disease development and progression by altering the immune status of the brain.

Keywords: blood brain barrier; brain arteriovenous malformation; cerebrovascular; endothelium; inflammation; microglia; neurovascular unit; vascular.

Figure 2

Cerebrovascular endothelium and lymphatics in the adult brain. (A) Schematic, sagittal view of the human brain (B) Coronal view of the brain, with the major middle cerebral arteries indicated in red. (C) Meningeal and cortical vascular networks within the brain. Within the dura, lymphatic blood vessels and fenestrated blood vessels lacking tight junctions allow for the transport of cells and molecules. The adjacent arachnoid, an epithelial layer, provides a barrier between the peripheral vasculature of the dura mater and the cerebral spinal fluid (CSF) via the presence of efflux pumps, channels, and tight junctions. Within the pia, leptomeningeal blood vessels, devoid of astrocytic ensheathment, are connected through tight junctions. Penetrating pial arteries located below that dura–arachnoid interface perfuse the underlying parenchymal tissue and are covered by a densely packed perivascular layer of astrocytic end feet and their processes, astrocytic (yellow), pial (pink), and endothelial (red/blue) basement membranes; and smooth muscle cells. (D) A capillary venule surrounded by the capillary endothelial basement membrane (purple) and the astrocytic basement membrane (pink). In contrast, the post-capillary venule contains a CSF fluid-filled perivascular space between the two membranes. Fibroblast-like cells (blue) line the astrocytic basement membrane of the post-capillary venule, serving as an extension of the pia mater. (E) The blood–CSF barrier is formed by tight joints in the choroid plexus. Within the choroid plexus, vessels are fenestrated to allow for molecular exchange. (F) The vasculature surrounding the perimeter of circumventricular organs is surrounded by a BBB with the astrocytic foot process, similar to vessels within CNS parenchyma. While the vessels themselves are fenestrated, ependymal tancycytes surround CVOs and contain tight junctions preventing CSF movement. Abbreviations: CVO = circumventricular organ, TJs = tight junctions, and CSF = cerebral spinal fluid. Figure adapted from [118].

Figure 1

Brain arteriovenous malformations. (A) Schematic view of bAVM vs. normal vasculature. (B) Simplified schematic of unruptured right parietal bAVM in 59-year-old female with MCA and ACA feeding arteries. Surgical resection of bAVM. (C_i) A parietal craniotomy being performed to gain access to the brain for the microsurgical resection of the lesion, with the feeding arterial supply from the ACA being apparent on the surface of the brain, as well as the arterialized draining vein. (C_ii) Feeding arteries being are circumferentially dissected and cauterized. The primary draining vein is initially left attached. It is severed after complete arterial supply to the nidus has been cut. (C_iii) ACA feeders being clipped. (C_iv) Arterialized draining vein being clipped. (C_v) Nidus being resected. (C_vi) Parenchyma after the nidus is removed. (D) Angiogram (carotid artery dye injection, lateral view) of a 2 cm brain arteriovenous malformation (Spetzler–Martin grade 1), of a patient 59 years of age, before surgical intervention. (E) Angiogram post-resection. Abbreviations: SSS = superior sagittal sinus, ISS = inferior saggital sinus, PCA = posterior cerebral artery, TS = transverse sinus, JV = jugular vein, BA = basilar artery, ICA = internal carotid artery, ACA = anterior cerebral artery, MCA = middle cerebral artery.

Figure 3

The blood–brain barrier (BBB) and neurovascular unit (NVU). (A) In the case of the microvasculature, the NVU is composed of endothelial cells, vascular smooth muscle cells, pericytes, and astrocytic endfeet, and serves as the building block of the BBB. (B) Within the endothelium, adhesion junctions, consisting of catenins and cadherins, mediate cell-to-cell adhesion, while tight junctions, consisting of occludins, claudins, JAMS 1–3, cingulin, and linker proteins of the ZO-1 family, together limit the passage of cells and molecules from the vessel lumen to the underlying brain parenchyma. This unique repertoire of junctional and adhesion proteins, along with the presence of a suite of transporters and efflux pumps, are core features of the blood–brain barrier.

Figure 4

Endothelial recruitment of leukocytes to the CNS. Five main steps are used in the process of leukocyte recruitment to the CNS: (1) Rolling: the endothelium slows leukocytes through interactions between VCAM-1 and P-selectin on endothelial cells and VLA-4 and PSGL-1 on the leukocyte. (2) Activation: chemokines interact with the leukocytic chemokine receptor, activating the leukocyte. (3) Arrest: The leukocyte then upregulates VLA-4 and LFA-1 (with LFA-1 binding to endothelial ICAM-1). This allows for leukocytic attachment to the endothelial cell. (4) Crawling: the arrested, activated leukocyte crawls along the endothelium to a paracellular or transcellular pathways. (5) Migration: Chemokines in the lumen allow the leukocyte to cross the endothelium to the perivascular space. Abluminal chemokines then allow leukocytes to migrate to the CNS. Figure adapted from [172].