Elsevier

Neurochemistry International

Volume 126, June 2019, Pages 126-138
Neurochemistry International

Defective vascular signaling & prospective therapeutic targets in brain arteriovenous malformations

https://doi.org/10.1016/j.neuint.2019.03.002Get rights and content

Highlights

  • Normal cerebrovascular function requires coordination of multiple cell types.

  • Brain AVMs are high flow arterial-venous shunts which may rupture.

  • Brain AVMs arise from abnormalities in TGF-β, VEGF, NOTCH or other signaling pathways.

  • New therapies are being developed to target disrupted signaling pathways in brain AVMs.

Abstract

The neurovascular unit is composed of endothelial cells, vascular smooth muscle cells, pericytes, astrocytes and neurons. Through tightly regulated multi-directional cell signaling, the neurovascular unit is responsible for the numerous functionalities of the cerebrovasculature – including the regulation of molecular and cellular transport across the blood-brain barrier, angiogenesis, blood flow responses to brain activation and neuroinflammation. Historically, the study of the brain vasculature focused on endothelial cells; however, recent work has demonstrated that pericytes and vascular smooth muscle cells – collectively known as mural cells – play critical roles in many of these functions. Given this emerging data, a more complete mechanistic understanding of the cellular basis of brain vascular malformations is needed. In this review, we examine the integrated functions and signaling within the neurovascular unit necessary for normal cerebrovascular structure and function. We then describe the role of aberrant cell signaling within the neurovascular unit in brain arteriovenous malformations and identify how these pathways may be targeted therapeutically to eradicate or stabilize these lesions.

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)

  • C. Iadecola

    The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease

    Neuron

    (2017)
  • N.J. Abbott et al.

    Astrocyte-endothelial interactions at the blood-brain barrier

    Nat. Rev. Neurosci.

    (2006)
  • A.A. Abla et al.

    Silent arteriovenous malformation hemorrhage and the recognition of "unruptured" arteriovenous malformation patients who benefit from surgical intervention

    Neurosurgery

    (2015)
  • R. Al-Shahi et al.

    A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults

    Brain

    (2001)
  • A. Armulik et al.

    Pericytes regulate the blood-brain barrier

    Nature

    (2010)
  • T.D. Arnold et al.

    Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking alphaVbeta8-TGFbeta signaling in the brain

    Development

    (2014)
  • R.D. Bell et al.

    SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells

    Nat. Cell Biol.

    (2009)
  • R.D. Bell et al.

    Apolipoprotein E controls cerebrovascular integrity via cyclophilin A

    Nature

    (2012)
  • A. Bharatha et al.

    Brain arteriovenous malformation multiplicity predicts the diagnosis of hereditary hemorrhagic telangiectasia: quantitative assessment

    Stroke

    (2012)
  • R. Blanco et al.

    VEGF and Notch in tip and stalk cell selection

    Cold Spring Harb Perspect Med

    (2013)
  • P.K. Brastianos et al.

    Dramatic response of BRAF V600E mutant papillary craniopharyngioma to targeted therapy

    J. Natl. Cancer Inst.

    (2016)
  • S.J. Bray

    Notch signalling: a simple pathway becomes complex

    Nat. Rev. Mol. Cell Biol.

    (2006)
  • Cancer Genome Atlas Research et al.

    Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas

    N. Engl. J. Med.

    (2015)
  • T.R. Carlson et al.

    Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice

    Proc. Natl. Acad. Sci. U. S. A.

    (2005)
  • P. Carmeliet et al.

    Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele

    Nature

    (1996)
  • P. Carmeliet et al.

    Molecular mechanisms and clinical applications of angiogenesis

    Nature

    (2011)
  • N. Chalouhi et al.

    Biology of intracranial aneurysms: role of inflammation

    J. Cereb. Blood Flow Metab.

    (2012)
  • S. Chasseigneaux et al.

    Isolation and differential transcriptome of vascular smooth muscle cells and mid-capillary pericytes from the rat brain

    Sci. Rep.

    (2018)
  • W. Chen et al.

    Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain

    Arterioscler. Thromb. Vasc. Biol.

    (2013)
  • W. Chen et al.

    De novo cerebrovascular malformation in the adult mouse after endothelial Alk1 deletion and angiogenic stimulation

    Stroke

    (2014)
  • Y. Chen et al.

    Evidence of inflammatory cell involvement in brain arteriovenous malformations

    Neurosurgery

    (2008)
  • Z.L. Chen et al.

    Ablation of astrocytic laminin impairs vascular smooth muscle cell function and leads to hemorrhagic stroke

    J. Cell Biol.

    (2013)
  • O.L. Chinot et al.

    Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma

    N. Engl. J. Med.

    (2014)
  • E.J. Choi et al.

    Novel brain arteriovenous malformation mouse models for type 1 hereditary hemorrhagic telangiectasia

    PLoS One

    (2014)
  • E.J. Choi et al.

    Minimal homozygous endothelial deletion of Eng with VEGF stimulation is sufficient to cause cerebrovascular dysplasia in the adult mouse

    Cerebrovasc. Dis.

    (2012)
  • D.N. Clarke et al.

    Perlecan Domain V induces VEGf secretion in brain endothelial cells through integrin alpha5beta 1 and ERK-dependent signaling pathways

    PLoS One

    (2012)
  • K. Cohen-Kashi-Malina et al.

    Mechanisms of glutamate efflux at the blood-brain barrier: involvement of glial cells

    J. Cereb. Blood Flow Metab.

    (2012)
  • V. Coric et al.

    Targeting prodromal alzheimer disease with avagacestat: a randomized clinical trial

    JAMA Neurol

    (2015)
  • S.I. Cunha et al.

    Deregulated TGF-beta/BMP signaling in vascular malformations

    Circ. Res.

    (2017)
  • R. Daneman et al.

    Pericytes are required for blood-brain barrier integrity during embryogenesis

    Nature

    (2010)
  • R.B. Davis et al.

    Notch signaling pathway is a potential therapeutic target for extracranial vascular malformations

    Sci. Rep.

    (2018)
  • D. Delev et al.

    NOTCH4 gene polymorphisms as potential risk factors for brain arteriovenous malformation development and hemorrhagic presentation

    J. Neurosurg.

    (2017)
  • L. Diaz-Flores et al.

    Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche

    Histol. Histopathol.

    (2009)
  • L. Diaz-Flores et al.

    Behavior of postcapillary venule pericytes during postnatal angiogenesis

    J. Morphol.

    (1992)
  • D. Ding et al.

    Radiosurgery for unruptured brain arteriovenous malformations: an international multicenter retrospective cohort study

    Neurosurgery

    (2017)
  • L.P. Diniz et al.

    Astrocytes and the TGF-beta 1 pathway in the healthy and diseased brain: a double-edged sword

    Mol. Neurobiol.

    (2018)
  • P. Dore-Duffy et al.

    CNS microvascular pericytes exhibit multipotential stem cell activity

    J. Cereb. Blood Flow Metab.

    (2006)
  • A. Dubrac et al.

    NCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy

    Nat. Commun.

    (2018)
  • J.E. Eckel-Passow et al.

    Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors

    N. Engl. J. Med.

    (2015)
  • H.M. Eilken et al.

    Pericytes regulate VEGF-induced endothelial sprouting through VEGFR1

    Nat. Commun.

    (2017)
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