# Cadherin Regulation in Dermal Endothelial Cells

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2020 · $451,039

## Abstract

The cutaneous microcirculation plays a central role in a range of skin diseases that are characterized
by epidermal hyperproliferation or inflammation. Many of these diseases are typified by increased
vascular permeability, which causes cutaneous edema and exacerbation of disease. In addition,
altered vascular organization and/or neovascularization are associated with psoriasis, skin
tumorigenesis, and with tissue remodeling during wound healing. Adhesive interactions between
adjacent endothelial cells play a central role in both vascular permeability and in the reorganization
and growth of endothelial cells during angiogenesis. VE-cadherin is a cell surface adhesion molecule
specific to endothelial cells and plays a crucial role in endothelial growth control, vascular barrier
function and in morphogenic events associated with angiogenesis. The extracellular domain of VE-
cadherin mediates cell to cell contact, whereas the cytoplasmic tail of VE-cadherin binds to a series of
proteins termed catenins, which couple VE-cadherin to actin and regulate VE-cadherin adhesion. Our
work has shown that p120-catenin is a VE-cadherin binding partner that associates with the cadherin
tail and prevents VE-cadherin endocytosis and degradation. Further, conditional gene ablation
experiments showed that deletion of endothelial p120-catenin leads to vascular malformations and
hemorrhage during development. Recently, we found that E3 ubiquitin ligases target VE-cadherin for
endocytosis and degradation. Thus, cadherin endocytosis is highly regulated and appears to be
important for vascular patterning and function. Here, we will explore the function of two different
endocytic signals in the VE-cadherin tail that we have recently identified. We hypothesize that VE-cad
endocytosis confers adhesive plasticity that is necessary for endothelial cell polarity and migration
during normal vascular development, and that ubiquitin ligases cause aberrant VE-cad endocytosis
and degradation. Aim 1 studies will use a series of approaches in both cell culture and in mouse
genetic models to determine how VE-cadherin endocytosis regulates endothelial cell polarity and
migration, and how these processes contribute to normal vascular development. Aim 2 studies will
focus on a MARCH family E3 ubiquitin ligase expressed in Kaposi sarcoma endothelial tumors.
Further, we will identify the endogenous MARCH family E3 ligases that are expressed in endothelial
cells and which target VE-cadherin for degradation during development and skin disease. Completion
of these studies will advance our understanding of cadherin based adhesion mechanisms and reveal
possible therapeutic targets to regulate angiogenesis and inappropriate vascular regression.

## Key facts

- **NIH application ID:** 10270771
- **Project number:** 7R01AR050501-17
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** ANDREW P. KOWALCZYK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $451,039
- **Award type:** 7
- **Project period:** 2004-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10270771

## Citation

> US National Institutes of Health, RePORTER application 10270771, Cadherin Regulation in Dermal Endothelial Cells (7R01AR050501-17). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10270771. Licensed CC0.

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