Defective vascular signaling & prospective therapeutic targets in brain arteriovenous malformations
Introduction
Neuronal function requires a constant supply of oxygen, glucose and other nutrients to meet metabolic needs, while ensuring clearance of toxic metabolic waste products. Neuronal metabolic demands are not static, but rather change as a result of functional activation and synaptic transmission on a cellular level. Complex neurologic tasks – such as speech, movement or sensation – requires activation and coordination of millions or possibly billions of cells in vast integrative networks (Herculano-Houzel, 2009). As a result, the brain utilizes roughly 20% of the body's oxygen and glucose, and disruption of blood flow may have profound effects on neuronal function and viability within minutes (Iadecola, 2017; Kisler et al., 2017a; Sweeney et al., 2018a, 2018b).
To meet this need, a vast integrated networking of tapering and branching blood vessels has evolved. The large muscular arteries which give rise to the cerebrovasculature arise off the aortic arch and form an anastomotic circle in the subarachnoid space along the base of the brain – known as the Circle of Willis (Menshawi et al., 2015). The large muscular arteries then progressively taper and form pial arteries along the brain surface. These arteries in turn dive into the brain parenchyma as penetrating arteries which progressively arborize to give rise to arterioles and ultimately the expansive capillary network tasked with molecular exchange between blood and brain (Iadecola, 2017; Zhao et al., 2015). The brain is a densely vascular organ; estimates have suggested that the capillary-to-neuron ratio is nearly 1:1, and neurons rarely exceed a distance of 15 μm from an adjacent capillary (Tsai et al., 2009). Capillaries coalesce into postcapillary venules, which further coalesce to form veins that ultimately drain into the venous sinuses. The venous sinuses in turn allow egress of blood out of the cranium back into the systemic circulation for re-oxygenation and filtration or removal of metabolic waste products (Kilic and Akakin, 2008).
This vast vascular network, however, is not a series of passive conduits. Rather, multicellular processes, such as sprouting angiogenesis and neurovascular coupling, allow dynamic remodeling of vascular structure and the functional allocation of blood flow to meet ever changing neuronal metabolic needs (Iadecola, 2017; Kisler et al., 2017a; Sweeney et al., 2018a, 2018b). These processes rely on coordinated signaling through multiple interconnected cell types. Cerebral blood vessels are anatomically comprised of endothelial cells, vascular smooth muscle cells, and pericytes, which are embedded in an extensive protein-rich extracellular matrix known as the vascular basement membrane (Winkler et al., 2011, 2014) (Fig. 1). Functionally, vascular cells are in tight juxtaposition and in constant communication with neurons, astrocytes, and inflammatory cells (microglia, perivascular macrophages and blood-borne leukocytes) (Abbott et al., 2006; Iadecola, 2017; Ransohoff, 2016). This has led to the coining of the term “neurovascular unit” to emphasize the functional interdependence between cell types (Iadecola, 2017; Zlokovic, 2005). In the ensuing subsections, the cellular components of the vasculature and key molecular pathways are summarized to provide a mechanistic understanding of distinct cerebrovascular functionalities. Thereafter, we describe how disruptions in normal cellular function contribute to formation of brain arteriovenous malformations and identify pathways for future therapeutic drug development.
Section snippets
Endothelial cells
Brain endothelial cells form a one cell thick lining of the vascular lumen, serving as the vital interface between blood and brain known as the blood-brain barrier (BBB) (Sweeney et al., 2018b; Zlokovic, 2008). Unlike systemic vessels, the endothelial membrane is continuous and without interruption with rare exception – such as discrete circumventricular organs (Kaur and Ling, 2017). Brain endothelial cells are connected through tight and adherens junctional protein complexes, which limit
Angiogenesis
Angiogenesis is the process of generating new blood vessels from pre-existing vessels and relies on coordinated paracrine cell signaling and direct contact between pericytes and endothelial cells. Two forms of angiogenesis have been proposed: endothelial sprouting and non-sprouting/intussusceptive, which is characterized by the splitting of pre-existing vessels by transcapillary pillars (Groppa et al., 2018; Risau, 1997). Here, we will focus on mechanisms of sprouting angiogenesis – the
Endothelial cells
To date, most bAVM research has focused on the endothelium. On histologic evaluation, significant endothelial heterogeneity has been described (Fig. 2). Endothelial cells can be either single- or multi-layered, and frequently display a hyperactive, immature phenotype with filopodia, cytoplasmic vesicles and vacuolization (Tu et al., 2006b). Even within the same blood vessel, however, adjacent segments may be characterized by endothelial hypoactivity and microvascular collapse or endothelial
Molecular pathways implicated in brain arteriovenous malformations
Numerous changes in gene expression have been described within bAVMs (Hashimoto et al., 2004; Shenkar et al., 2003). Less than ∼5% of arteriovenous malformations are associated with autosomal dominant disorders – such as such as hereditary hemorrhagic telangiectasia (HHT) and capillary malformation-arteriovenous malformation syndrome (CAMS) (Walcott et al., 2016). Generation of rodent models of these genetic syndromes or alterations in other molecular pathways implicated in bAVMs have begun to
Transforming growth factor receptor beta (TGF-β)
Transforming growth factor beta (TGF-β) is a multifunctional cytokine which has multiple effects on brain vascular development implicated in vascular malformations – including both bAVMs and cavernous malformations (Cunha et al., 2017; Gaengel et al., 2009; Sweeney et al., 2016). Latent TGF-β is secreted by endothelial cells, pericytes, neurons and astrocytes, and is activated by thrombospondin or integrins in the extracellular space (Lebrin et al., 2005). Activated TGF-β binds to a type 2
Future directions
Advances in next generation sequencing technologies have led to identification of unrecognized genetic mutations which contribute to the genesis of bAVMs – such as KRAS, BRAF and SMAD9 (Hong et al., 2019; Nikolaev et al., 2018; Walcott, 2014). Development of new rodent models utilizing newer techniques, such as CRISPR, have begun to be undertaken (Zhu et al., 2018b). Genetically engineered rodents harboring newly identified mutations, such as KRAS or BRAF, may offer the first model of sporadic
Conflicts of interest
None.
References (204)
- et al.
Pericytes: developmental, physiological, and pathological perspectives, problems, and promises
Dev. Cell
(2011) - et al.
Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging
Neuron
(2010) - et al.
Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia
Neuroscience
(2009) - et al.
Reck and Gpr124 are essential receptor cofactors for Wnt7a/Wnt7b-specific signaling in mammalian CNS angiogenesis and blood-brain barrier regulation
Neuron
(2017) - et al.
Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival
Dev. Biol.
(2003) - et al.
Pericyte ALK5/TIMP3 Axis contributes to endothelial morphogenesis in the developing brain
Dev. Cell
(2018) - et al.
Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial
Lancet Oncol.
(2017) - et al.
Pericytes promote endothelial cell survival through induction of autocrine VEGF-A signaling and Bcl-w expression
Blood
(2011) Notch signaling in the vasculature
Curr. Top. Dev. Biol.
(2010)- et al.
Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes
Neuron
(2015)