title: Notch signaling in vascular smooth muscle cells is required to pattern the cerebral vasculature.
abstract: Stroke is the third leading cause of death and a significant contributor of morbidity in the United States. In humans, suboptimal cerebral collateral circulation within the circle of Willis (CW) predisposes to ischemia and stroke risk in the setting of occlusive carotid artery disease. Unique genes or developmental pathways responsible for proper CW formation are unknown. Herein we characterize a mouse model lacking Notch signaling in vascular smooth muscle cells (vSMCs), in which the animals are intolerant to reduced cerebral blood flow. Remarkably, unilateral carotid artery ligation results in profound neurological sequelae and death. After carotid ligation, perfusion of the ipsilateral cerebral hemisphere was markedly diminished, suggesting an anastomotic deficiency within the CW. High-resolution microcomputed tomographic (micro-CT) imaging revealed profound defects in cerebrovascular patterning, including interruption of the CW and anatomic deformity of the cerebral arteries. These data identify a vSMC-autonomous function for Notch signaling in patterning and collateral formation within the cerebral arterial circulation. The data further implicate genetic or functional deficiencies in Notch signaling in the pathogenesis of anatomic derangements underlying cerebrovascular accidents.
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Proweller
authors.forename: Alex C
authors.initials: AC
authors.lastname: Wright
authors.forename: Debra
authors.initials: D
authors.lastname: Horng
authors.forename: Lan
authors.initials: L
authors.lastname: Cheng
authors.forename: Min Min
authors.initials: MM
authors.lastname: Lu
authors.forename: John J
authors.initials: JJ
authors.lastname: Lepore
authors.forename: Warren S
authors.initials: WS
authors.lastname: Pear
authors.forename: Michael S
authors.initials: MS
authors.lastname: Parmacek
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000502:physiology; D001921:Brain / Q000098:blood supply* / Q000254:growth & development; D002536:Cerebral Arteries / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D002941:Circle of Willis / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000254:growth & development / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology; D018919:Neovascularization, Physiologic; D051880:Receptors, Notch / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D051880:Receptors, Notch