# Epsin in Angiogenesis and Vascular Remodeling

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $882,499

## Abstract

Project Summary/Abstract
Pathological angiogenesis is a key process that drives vascular remodeling in numerous cardiovascular and
metabolic diseases including diabetic retinopathy, age-related macular degeneration (AMD) and cancer.
However, owing to scarcity of proper molecular targets, it is widely recognized that hindering pathological
angiogenesis to mitigate these deleterious disease conditions remains daunting. Our long-term goal is to
uncover original molecular mechanisms and identify fresh molecules that prevent pathological angiogenesis in
hopes of offering potential new therapeutic approaches. In our last funding cycle, we examined the role of
endothelial epsins and Dab2 in reciprocally regulating VEGF signaling and created mice with either inducible
endothelial-specific epsins 1 and 2 deficiency (EC-iDKO) or endothelial-specific Dab2 deficiency (EC-
Dab2iKO). We showed that epsins and Dab2 interact with VEGFR2 via a mutually exclusive mechanism.
Interestingly, mice lacking endothelial epsins and Dab2 (EC-iTKO) rescue heightened angiogenesis caused by
epsins depletion, or attenuated angiogenesis produced by Dab2 loss, suggesting that epsins and Dab2
antagonizing each other to modulate VEGF-mediated angiogenesis in vivo. Given that VEGF signaling plays a
central role in normal, as well as pathological angiogenesis, how epsin and Dab2 are differentially recruited to
mediate VEGFR2 internalization and modulate VEGF signaling is a highly significant and open question. In
searching for upstream signals that preferentially trigger either epsin or Dab2 binding to VEGFR2, our latest
study revealed that Sphigosine 1 Phosphate (S1P) stimulation facilitates epsins but hinders Dab2 binding to
VEGFR2, leading to VEGF-induced VEGFR2 degradation. How S1P selectively allows the recruitment of
epsins to VEGFR2 is poorly understood. Further, we discover that miRNA (miR-19) directly binds epsins'
3'UTR and represses epsins' expression. Whether miR-19 potentiates VEGF signaling by inhibiting epsins'
expression is entirely unclear. Given crucial roles epsins play in regulating angiogenesis, uncovering molecule
mechanisms and genetic modifiers that control epsins' activity and govern epsin expression may offer new
therapeutic approaches in pathological angiogenesis. To this end, we hypothesize that S1P induced Src
activation phosphorylates VEGFR2, enabling VEGFR2:Cbl association and VEGFR2 ubiquitination, and
enforcing epsin:VEGFR2 binding and VEGFR2 downregulation. We further hypothesize that epigenetic
regulation including miR-19 that directly suppresses epsins' expression, causing heightened VEGF signaling.
We will utilize multifactorial approaches to investigate molecular mechanisms responsible for regulating epsin's
activity and expression. Lastly, we will determine therapeutic potential of enhancing epsin or S1P function in
pathological angiogenesis. If fruitful, our findings will advance our understanding of novel pathways and targets
that modulate VE...

## Key facts

- **NIH application ID:** 9964872
- **Project number:** 5R01HL093242-12
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Hong Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $882,499
- **Award type:** 5
- **Project period:** 2009-07-17 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964872

## Citation

> US National Institutes of Health, RePORTER application 9964872, Epsin in Angiogenesis and Vascular Remodeling (5R01HL093242-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9964872. Licensed CC0.

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