# Novel role of integrins in paracrine regulation of vasculature

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $617,218

## Abstract

Abstract.
This proposal aims to understand the nature of the crosstalk between vascular and resident innate immune cells
(microglia) in order to normalize dysfunctional (insufficient or excessive) vasculature and to develop novel tissue
regeneration and revascularization technologies. It addresses the basic functions of microglia, which plays a
coordinating role in numerous pathologies from developmental abnormalities and behavioral problems to
neurodegenerative disorders to neuropathology of HIV. Using microglia-specific Kindlin3 and integrin knockouts,
we show that despite the normal presence in brain and retinas, Kindlin deficient microglia is characterized by
deregulated production of angiogenic factors. As a result, retinal vasculature in microglia-specific KOs has
abnormally dense and irregular vascular pattern and exhibits excessive growth of blood vessels into the normally
avascular area of photoreceptors. We show that this is mediated by overproduction of TGFβ1 by K3KO microglia,
since knockout of microglial TGFβ1 in K3KO mice rescues this vascular phenotype. Mechanistically, while
normal microglia “switches off” its production of TGFβ1 in matrix with higher ligand density or higher stiffness,
this mechano-switch is abrogated in Kindlin3 deficient microglia. We show that the mechanosensory function of
microglia depends on the membrane-to-cortex attachment (MCA) complex, which is disrupted by the lack of
Kindlin3. We demonstrate that Kindlin3 binds not only to integrin, to plasma membrane but also connects to
cytoskeleton (by direct binding to leupaxin/paxillin) and disruption of K3-paxillin binding disrupts MCA complex.
These results led us to formulate a novel paradigm-changing hypothesis that: Kindlin3 coordinates MCA
complex, which, in turn, orchestrates the mechanosensory function of microglia, i.e. its ability to respond to the
mechanical properties of ECM by the changes in angiogenic factors expression. The mechanistic question: “How
exactly microglia is able to sense the ECM properties in order to regulate vasculature?” will be answered in this
proposal. Aim 1. To test the hypothesis that paracrine regulation of angiogenesis is controlled by β1 rather than
β2 integrin on microglia and requires a fully functional complex between integrin and Kindlin3, which, in turn,
regulates microglial expression of TGFβ. Aim 2. To test a hypothesis that integrin-kindlin3-leupaxin/paxillin
complex functions as a sensor of membrane tension and as a result, ECM composition and mechanical
properties and to define the structure-functional determinants of this complex. We will utilize our recently
developed 3D hydrogel-based system with controlled mechanical characteristics (ligand density, stiffness and a
relaxation time). Our new in vitro technologies will lead to the development of novel materials and approaches
for tissue regeneration and microglia-controlled revascularization. The knowledge of microglia will lead to new
treatments for multiple sc...

## Key facts

- **NIH application ID:** 10200117
- **Project number:** 5R01HL071625-17
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Tatiana V Byzova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $617,218
- **Award type:** 5
- **Project period:** 2003-07-14 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200117

## Citation

> US National Institutes of Health, RePORTER application 10200117, Novel role of integrins in paracrine regulation of vasculature (5R01HL071625-17). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10200117. Licensed CC0.

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