title: Regulation of pre-natal circle of Willis assembly by vascular smooth muscle Notch signaling.
abstract: The circle of Willis (cW) is a major arterial collateral structure interconnecting hemispheric circulation within the brain, and in humans, anatomical variation of the cW is linked to stroke risk. Our prior studies on adult mice deficient in vascular smooth muscle cell (vSMC) Notch signaling revealed altered cerebroarterial maturation and patterning, including an anatomically incompetent cW similar to human variants. However, a developmental dependency on Notch signaling for cW formation in this model remained uncharacterized. Through temporospatial embryonic analyses, we now demonstrate that cW assembly is a pre-natal process highly sensitive to vSMC Notch signals, whose absence results in delayed nascent vascular plexus formation and under-development of the cW including the key anterior communicating artery (AComA) interconnecting anterior forebrain circulation. Mutant embryos additionally feature reduced vSMC coverage, non-uniform calibers and asymmetric branching at bifurcations of the major proximal cerebral arteries. At the cellular level, a notable reduction in vascular endothelial cell proliferation exists in the region of AComA assembly despite the presence of Vegfa. Furthermore, Notch signaling-deficient vSMCs in developing cerebral vessels feature reduced Pdgfrβ and Jagged1 levels and impaired proliferation. These collective findings in the embryonic brain support studies in adult animals demonstrating a reliance on intact vSMC Notch signaling for optimal neovascular responses to angiogenic stimuli. Importantly, the new data provide unique insights into the native formation of the cW and underscore a pioneering developmental role for vSMC Notch signaling in regulating temporospatial assembly of the clinically relevant cW.
authors.affiliation: Case Cardiovascular Research Institute and University Hospitals Harrington Heart and Vascular Institute, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.forename: Suhanti
authors.initials: S
authors.lastname: Banerjee
authors.forename: Aaron
authors.initials: A
authors.lastname: Proweller
mesh_terms: D000818:Animals; D001158:Arteries / Q000196:embryology; D049109:Cell Proliferation; D002941:Circle of Willis / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D008024:Ligands; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009154:Mutation; D009389:Neovascularization, Pathologic; D016548:Prosencephalon / Q000196:embryology; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D008024:Ligands; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: ACA; AComA; Angiogenesis; BA; Circle of Willis; ICA; MCA; Notch signaling; OA; PC; PCA; PComA; Pdgf; Pdgfrβ; Vascular smooth muscle cell; Vegfa; Vegfr-2; anterior cerebral artery; anterior communicating artery; basilar artery; cW; circle of Willis; internal carotid artery; middle cerebral artery; ophthalmic artery; pericyte; platelet derived growth factor receptor beta; platelet derived growth factor-bb; posterior cerebral artery; posterior communicating artery; vSMC; vascular endothelial growth factor receptor-2; vascular endothelial growth factor-a; vascular smooth muscle cell