Vascular smooth muscle cells (VSMCs) support the formation, structural integrity and chemical responsivity required for development, post-natal maturation and function of the blood vasculature. Following the process of vasculogenesis wherein endothelial cells (ECs) coalesce to form a primitive, tubular capillary network, recruitment of VSMCs promotes vessel maturation or angiogenic remodeling governed by a complex interplay of signaling and transcriptional programs operating within ECs and VSMCs. The balance of these activities critically regulates vascular formation and function under physiologic and pathologic conditions. Previous studies published by the PI revealed that suppression of canonical Notch signaling in VSMCs in vivo resulted in improper cerebral arterial patterning as well as failure to form mature arterial vessel walls. These findings identified a VSMC-autonomous role for Notch signaling in the formation of competent vessels and implicated an important role for Notch signaling in arterial patterning and collateral artery formation. In addition, these anatomical derangements were associated with an increased risk for cerebrovascular insufficiency and stroke in mice subjected to induced ischemia. Taken together, these observations support our central hypothesis that Notch signaling in VSMCs provides instructive cues required for proper organization and function of the arterial vasculature. The goal of this proposal is to further study, in a comprehensive manner, the role of Notch signaling in VSMC biology in vitro and in vivo.
In Aim 1, studies in mouse embryos harboring Notch signaling-deficient VSMCs will be undertaken to map the temporal-spatial organization of emerging vessels during pre-natal development as a basis for the observed post-natal anatomical abnormalities.
Aim 2 will address the functional dynamics of Notch signaling-deficient VSMCs within native vessels by examining vasoreactive responses to physiological and chemical stimuli important for cerebral and peripheral vascular homeostasis. Finally, Aim 3 will examine the molecular basis for altered vessel structure and VSMC function in part through ex vivo and in vitro studies assessing the angiogenic and vessel remodeling contributions of Notch signaling-deficient VSMCs.

Public Health Relevance

Vascular smooth muscle cells (VSMCs) are required for the formation of a competent vascular system. Notch signaling is an important molecular pathway that regulates VSMC function and defects in Notch signaling are genetically linked to human vascular syndromes featuring stroke and congenital cardiovascular abnormalities. This proposal serves to identify at a mechanistic level the precise roles for Notch signaling in VSMCs that confer proper organization and function of the vasculature. The results from these investigations will provide the foundation for novel therapies for the treatment of vascular insufficiencies such as peripheral and cerebral arterial disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL096603-05
Application #
8467028
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Olive, Michelle
Project Start
2009-09-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$369,923
Indirect Cost
$134,303
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Hale, Andrew T; Tian, Hongmei; Anih, Ejike et al. (2014) Endothelial Kruppel-like factor 4 regulates angiogenesis and the Notch signaling pathway. J Biol Chem 289:12016-28
Yang, Ke; Banerjee, Suhanti; Proweller, Aaron (2013) Regulation of pre-natal circle of Willis assembly by vascular smooth muscle Notch signaling. Dev Biol 381:107-20
Basu, Sanchita; Srinivasan, Dinesh Kumar; Yang, Ke et al. (2013) Notch transcriptional control of vascular smooth muscle regulatory gene expression and function. J Biol Chem 288:11191-202
Han, Yu; Yang, Ke; Proweller, Aaron et al. (2012) Inhibition of ARNT severely compromises endothelial cell viability and function in response to moderate hypoxia. Angiogenesis 15:409-20
Yang, Ke; Proweller, Aaron (2011) Vascular smooth muscle Notch signals regulate endothelial cell sensitivity to angiogenic stimulation. J Biol Chem 286:13741-53