# Fluid shear stress mechanotransduction at endothelial cell-cell junctions

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $533,410

## Abstract

Project Summary
This project aims to understand in molecular detail how fluid shear stress acting on endothelial
cells triggers mechanical activation of signaling pathways at cell-cell junctions. Published data
show that shear stress activates a PECAM1-dependent signaling pathway, Notch signaling and
Alk1-Endoglin-Smad1/5 signaling, all of which occur at and depend on cell-cell contacts. These
pathways play major roles in vascular embryonic development, postnatal physiology and adult
disease. However, much remains to be learned about molecular mechanisms. The proposed
work is based on two recent advances in our labs. First, we have recently identified latrophilins
(LPHNs, also known as ADGRLs), members of the adhesion G protein coupled receptors
family, as key upstream mediators of shear activation of all three of these pathways. Second,
we have developed a new nanodevice that utilizes DNA origami to apply defined mechanical
tension to proteins. Aim 1 will investigate (1) the molecular mechanisms by which LPHNs
mediate the effects of shear stress on junctional signaling and (2) determine the role of LPHN2
in vascular development and function in vivo by doing endothelial-specific knockout in mice.
Aim 2 will use the DNA origami device to apply defined tension to PECAM1 and visualize
protein conformation change via cryoEM. These experiments will allow us to determine the
effect of applied force on PECAM’s structural transitions. Together, the project will provide new
understanding at unprecedented depth concerning how endothelial cell-cell junctional proteins
respond to mechanical force generated by shear stress.
.

## Key facts

- **NIH application ID:** 10322398
- **Project number:** 5R01HL155543-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Chenxiang Lin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $533,410
- **Award type:** 5
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322398

## Citation

> US National Institutes of Health, RePORTER application 10322398, Fluid shear stress mechanotransduction at endothelial cell-cell junctions (5R01HL155543-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10322398. Licensed CC0.

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