# Notch in Angiogenesis and Vascular Biology

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $475,913

## Abstract

Project Summary/Abstract
Endothelial Notch signaling drives essential and diverse functions in angiogenesis. Abnormal Notch
signaling is a significant contributor to many cardiovascular diseases; from blindness, stroke, and ischemic
disease, to arteriovenous malformation (AVM) and tumor angiogenesis. Notch genes encode
transmembrane receptors which undergo ligand-dependent cleavage of the intracellular domain; the
intracellular domain then translocates to the nucleus, where it assembles transcriptional complexes to
regulate the expression of downstream targets that carry out Notch function. Notch receptors respond to
two classes of membrane bound ligands, Delta-like (Dll) and Jagged (Jag). Dll4 signals through Notch in
normal and pathological angiogenesis to restrict sprout formation and promote perfusion, whereas Jag1
may have both Notch activating and inhibitory roles in endothelial cells. The transcriptional targets of Notch
signaling drive many cellular functions that are critical for proper angiogenesis, yet our knowledge of Notch
targets is currently limited. Defining these targets in the endothelium is needed to obtain a deeper
knowledge of Notch angiogenic function and identifying the novel effectors will impact our ability to
understand healthy vessels and human disease. Our preliminary studies highlight that Notch regulates
several endothelial proteins that function in GPCR signaling, an unexplored area of endothelial Notch
signaling. Our overall goal is to define endothelial genes regulated by Notch and use this knowledge to
identify Notch effectors that regulate GPCR signaling and their mode of action in the vasculature. In this
proposal, we will stimulate endothelial Dll4- or Jag1-Notch mediated transcription in vitro and identify Notch
targets by RNAseq. A RiboTag mouse model will determine Notch-responsive endothelial genes in vivo.
Combining data from the in vivo and in vitro analysis will lead to selection of candidate Notch targets that
function in GPCR pathways and these will be validated as direct transcriptional targets. Using in vitro co-
culture angiogenesis assays, we will determine if Notch-induced GPCR signaling molecules are required in
order for Notch to regulate sprouting angiogenesis. One such candidate, Rnd1, a constitutively active
GTPase, will be analyzed to test the hypothesis that Notch induces Rnd1 to regulate Rap-p120RasGAP-
Ras signaling in endothelial cells. Rnd1, and other GPCR proteins induced by Notch, will be studied in mice
to determine their roles in Notch regulated sprouting angiogenesis, hypoxia-induced retinopathy and
arteriovenous malformation (AVM).

## Key facts

- **NIH application ID:** 9843153
- **Project number:** 5R01HL112626-08
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Jan K. Kitajewski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $475,913
- **Award type:** 5
- **Project period:** 2012-07-17 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843153

## Citation

> US National Institutes of Health, RePORTER application 9843153, Notch in Angiogenesis and Vascular Biology (5R01HL112626-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9843153. Licensed CC0.

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