# Novel mechanism mediating LPA-induced smooth muscle cell and vascular responses

> **NIH NIH R01** · UNIVERSITY OF TEXAS OF THE PERMIAN BASIN · 2020 · $460,967

## Abstract

ABSTRACT
Vascular smooth muscle cell (SMC) migration is a critical event in neointimal formation in the development of
atherosclerosis and restenosis, Lysophosphatidic acid (LPA), is emerging as an important lipid mediator of the
cellular events contributing to atherosclerosis. During the last grant period, using an LPA receptor knockout
mouse model, we identified LPA receptor 1 as the major cell membrane receptor mediating LPA-induced SMC
migration and neointimal formation. We also discovered the matricellular protein Cyr61 as the key molecule
mediating LPA signaling, leading to SMC migration and neointimal formation. These findings established a new
concept that Cyr61 bridges the LPA and integrin signaling pathways, leading to focal adhesion kinase (FAK)
activation/SMC migration and neointimal formation. In this grant period, we propose to extend our investigation
to identify the molecular mechanism by which LPA-Cyr61 induces SMC migration and the LPA-Cyr61 pathway
contribution to atherogenesis. Very recently lineage-tracing studies reveal that a large portion of macrophage
marker-positive cells in mouse and human atherosclerotic lesions are vascular SMC-derived cells, suggesting
SMC migration/proliferation and differentiation play important roles in atherogenesis. Understanding of SMC
migration mechanism will significantly contribute to understanding atherogenesis. To date, little is known about
the nature and spatial-temporal regulation of the migration which drives kinases in the polarized leading edge
of SMCs. Interestingly, our recent study revealed several exciting novel findings: 1) the novel pseudopodium-
enriched atypical kinase 1 (PEAK1) activation is localized in the polarized leading edge of SMCs upon LPA
treatment; 2) Cyr61 induces PEAK1 activation and 3) knockdown of PEAK1 blocked SMC migration,
suggesting PEAK1 functions as a downstream key mediator of Cyr61, regulating SMC migration. Furthermore,
we discovered that PEAK1 interacts with FAK, a key regulator of cell migration. We also observed that
phosphorylated PEAK1 levels are highly increased in ApoE-/- atherosclerotic lesions. The function of the novel
kinase PEAK1 in vascular disease is unknown. Our data suggest that PEAK1 is the novel mediator for FAK
activation and SMC migration. Based on these new observations, we hypothesize that the LPA receptor-
Cyr61-integrin-PEAK1-FAK axis mediates SMC cytoskeleton reorganization/migration and lesion formation in
atherosclerosis. These hypotheses will be tested in the following specific aims. Aim 1: Determine the novel role
of PEAK1/FAK interaction on the activation of the Src/PEAK1/FAK/Paxillin/Rac pathway and SMC migration.
Aim 2: Dissect the novel mechanism by which Cyr61 interacts integrin-adhesion complex signaling, leading to
membrane protrusion and cell migration using unique Cyr61 mutant SMCs from novel Cyr61dm/dm knock-in
mice. Aim 3: Establish the roles of LPA receptors and Cyr61 in the development of atherosclerosis using ...

## Key facts

- **NIH application ID:** 9964878
- **Project number:** 5R01HL107466-08
- **Recipient organization:** UNIVERSITY OF TEXAS OF THE PERMIAN BASIN
- **Principal Investigator:** MEI-ZHEN CUI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $460,967
- **Award type:** 5
- **Project period:** 2018-06-08 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964878

## Citation

> US National Institutes of Health, RePORTER application 9964878, Novel mechanism mediating LPA-induced smooth muscle cell and vascular responses (5R01HL107466-08). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9964878. Licensed CC0.

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