# Arterial Vasoregulation by Notch Signaling

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $523,266

## Abstract

PROJECT SUMMARY/ABSTRACT
Vascular smooth muscle (SM) and endothelial cells (EC) coordinate the molecular signals governing arterial
vasoreactivity. The balance of constrictor and relaxant signals establishes vessel tone and directly influences
systemic blood pressure in health and disease. Our laboratory has uncovered novel and paradoxical roles for
Notch signaling in the vessel wall that influence arterial function. Specifically, SM Notch receptors triggered by
SM Jagged1 ligand promote myosin light chain kinase (MLCK) expression and Ca2+ sensitization inducing
myosin light chain (MLC) phosphorylation, the molecular signature of force production. Mice lacking SM
Jagged1 feature dysregulated blood pressure and pressor responses and arteries exhibit impaired force
generation. In contrast, EC Dll4 ligand stimulates expression of SM MYPT1, the regulatory subunit of myosin
phosphatase (MP), favoring dephosphorylation of MLC and a relaxant phenotype. Moreover, EC Dll4-deficient
arteries yield vasorelaxation deficits in a novel NO-independent manner. Together, these findings underscore
instructional Notch signaling through heterotypic (EC-SM) and homotypic (SM-SM) cell interactions in the
vessel wall and provide new knowledge in the molecular determinants of vasoregulation. The overall goal in
this new project proposal is to define the physiologically relevant Notch ligand/receptor that modulates distinct
arterial functions. In Aim 1, we determine the contribution of both SM and EC Jagged1 ligand and Notch1
receptor in regulation of constrictor and hemodynamic responses in vascular health and disease animal
models. Aim 2 delineates the physiological role and mechanism of EC Dll4 ligand in mediating arterial
relaxation. Finally, Aim 3 examines the molecular basis for Notch signaling-dependent control of myosin
phosphatase activity via Ca2+ sensitization and/or desensitization. Experimental approaches include a full
spectrum of in vivo, ex vivo and in vitro vascular analyses necessary for understanding relevant physiology and
novel molecular mechanisms through which Notch pathway components regulate arterial function.

## Key facts

- **NIH application ID:** 10399591
- **Project number:** 5R01HL151500-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** AARON PROWELLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $523,266
- **Award type:** 5
- **Project period:** 2021-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399591

## Citation

> US National Institutes of Health, RePORTER application 10399591, Arterial Vasoregulation by Notch Signaling (5R01HL151500-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10399591. Licensed CC0.

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