# Notch in Angiogenesis and Vascular Biology

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $608,853

## Abstract

Elucidating the signaling pathways that control angiogenesis allows new therapies to be designed for treatment
of diseases where blood vessels are contributors, including blindness, inflammation, and cancer. Notch1
signaling generally acts as a negative regulator of angiogenic sprouting. We hypothesize that Notch4, a Notch
receptor primarily expressed in endothelium, has both overlapping roles with Notch1 and distinct endothelial
functions. We demonstrated that Notch4 promotes angiogenesis and possibly inflammation of blood vessels and
surrounding cells. By removing Notch4 expression in blood vessels of mice or blocking Notch4 using an inhibitor,
we discovered that Notch4 promotes angiogenesis in the developing retina. Notch4 is expressed in blood vessels
of many types of tumors and we demonstrated that blocking Notch4 inhibits tumor growth when Notch4 is in
tumor vessels. We found that endothelial Notch4 appears to function to alter both vessels and adjacent stromal
tissue. Analysis of Notch4-regulated genes led us to discover that specific cytokine signaling proteins are
regulated by Notch4, and not Notch1, a possible mechanism for Notch4 broad influence on both vessels and
surrounding tissue. In these studies, we will define the unique signaling mechanisms regulated by Notch4 to
understand how Notch4 promotes developmental, inflammatory-driven, and tumor angiogenesis and evaluate
anti-Notch4 treatment for therapeutic benefit. We will use a new technique called CUT&RUN to see which genes
are directly activated by Notch4 or Notch1 and use a novel RiboFlag translational analysis to understand
expression control by each Notch protein. We will determine if newly discovered Notch4-regulated proteins
promote angiogenesis and inflammation in cultured endothelial cells and remove Notch4 expression from
endothelial cells in mice to determine if this causes reduced blood vessel growth, reduces the response to
inflammation and reduces tumor growth. We will separately remove Notch1 or Notch4 genes from endothelium
or remove both genes and describe result of Notch loss on developmental and pathological angiogenesis,
establishing unique and overlapping roles for these genes. A new Notch inhibitor allows us to investigate pre-
clinical therapeutic potential for treatment of proliferative retinopathy, an inflammatory eye disease, and in tumors
that have Notch4 in the endothelial cells. We will investigate the stromal changes in tumors caused by genetic
or pharmacologic blockade of Notch4 using flow cytometry and focused single cell RNA sequencing. In all of
these studies, we will determine if select cytokines are regulated by Notch4 in healthy and disease-associated
blood vessels, with the goal of understanding the mechanisms by which Notch4 impacts inflammation of blood
vessels and surrounding tissue or tumor. Our goals for this proposal will be to discover the unique ways that
Notch4 works to build normal blood vessels and contributes to diseased vessels, an...

## Key facts

- **NIH application ID:** 10585379
- **Project number:** 2R01HL112626-10A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Jan K. Kitajewski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $608,853
- **Award type:** 2
- **Project period:** 2012-07-17 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10585379

## Citation

> US National Institutes of Health, RePORTER application 10585379, Notch in Angiogenesis and Vascular Biology (2R01HL112626-10A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10585379. Licensed CC0.

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