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 (-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.angiogenesis ͉ cerebrovascular accident ͉ vascular patterning ͉ mastermind

Vascular Smooth Muscle Notch Signals Regulate Endothelial Cell Sensitivity to Angiogenic Stimulation

“…As a parallel to EC Notch signaling, the capacity for vSMCs to promote and engage in heterotypic contact and functionally influence neighboring cells in a Notch signaling-dependent manner is conceptually appealing, and recent reports utilizing Notch3-deficient tissues have begun to illuminate this possibility (26 -28). As reported previously, an adult murine model (SM22-Cre ϩ /DNMAML1 ϩ ) engineered to suppress canonical Notch signaling in smooth muscle exhibited defects in arterial maturation and cerebroarterial patterning, suggesting that vSMC-derived Notch signals can have a profound influence on proper arterial vessel formation (29). An important strength of this model is that it relies on the elaboration of a dominantnegative form of MAM (DNMAML1) to inhibit Notch signals transduced by all Notch receptors on vSMCs.…”

“…An important strength of this model is that it relies on the elaboration of a dominantnegative form of MAM (DNMAML1) to inhibit Notch signals transduced by all Notch receptors on vSMCs. Therefore, the sum output of canonical Notch activity is significantly blunted (29). By overcoming potential functional redundancies among Notch receptors, SM22-Cre ϩ /DNMAML1 ϩ mice may provide a more comprehensive characterization of the net effect of Notch signaling loss in vSMCs.…”

Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development

“…This suggests that the critical time period for Notch-dependent activation of cardiac precursor cell differentiation is prior to the expression of Islet1. In contrast, later inhibition of Notch with DNMAML using SM22α-Cre, which is active in second heart field myocardium only after migration into the heart proper, does not recapitulate structural cardiac disorders (16,49). Therefore, the critical time period for Notch activity in the second heart field for appropriate OFT patterning must be before SM22α-Cre can result in the effective expression of DNMAML.…”

The miR-143/145 Cluster Is a Novel Transcriptional Target of Jagged-1/Notch Signaling in Vascular Smooth Muscle Cells

“…Homotypic and heterotypic Notch signaling have been shown to be critical in defining vascular tone, maintaining vascular homeostasis, recruitment of mural cells and communication during angiogenesis (40). While Jag-1 expression in the endothelium activates Notch3 receptors in adjacent VSMC and promotes a mature contractile phenotype (15), Notch signaling between VSMC is also critical for mediating vascular remodeling after injury (41). It is likely that adjacent cell activation of VSMC Notch receptors by Jag-1 plays a pivotal role in regulating the miR-143/145 cluster and modulation of the VSMC phenotype.…”