The migration of vascular smooth muscle cells (VSMCs) is an essential event during atherosclerosis and restenosis after angioplasty. Cellular migration is achieved through coordinated regulation of membrane trafficking and cytoskeletal reorganization. While many studies have focused on the regulation of cytoskeletal reorganization in VSMCs, little is known about the involvement of membrane trafficking and the coordinated regulation of cytoskeletal reorganization and membrane trafficking in the migration of these cells. Our preliminary data have suggested that Phospholipase D2 (PLD2), a member of the phospholipase D family that generates the signaling lipid phosphatidic acid (PA), plays important roles in the migration, cytoskeletal reorganization, and membrane trafficking in VSMCs. Using a combination of liposome pull-down and mass spectrometry, we also identified some new PA-binding proteins, which have revealed the novel mechanistic insights into the cellular functions of PA. Based on our findings, we propose that PLD2-generated PA coordinately regulate cytoskeletal reorganization and membrane trafficking during VSMC migration. By using some newly available reagents and a unique interdisciplinary approach including molecular and cell biology, lipid biology, and animal models, we will investigate the mechanisms by which PLD2 regulates VSMC migration in vitro, and then examine how PLD2-regulated cell migration contributes to injury-induced vascular remodeling using mouse models.
Three aims are proposed.
In Aim 1, we will examine the roles of PLD2 in the polarization and migration of VSMCs.
In Aim 2, we will elucidate the mechanisms by which PLD2-controlled membrane trafficking regulates VSMC migration.
In Aim 3, we will investigate if PLD2 regulates vascular remodeling in vivo.

Public Health Relevance

The results of these studies will identify novel molecular and cellular mechanisms that underlie VSMC migration, and thus, may lead to the development of new therapeutic treatments for cardiovascular diseases related to VSMC migration such as atherosclerosis and restenosis after angioplasty.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL119478-01A1
Application #
8696936
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Olive, Michelle
Project Start
2014-04-01
Project End
2018-01-31
Budget Start
2014-04-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$380,000
Indirect Cost
$130,000
Name
University of Texas Health Science Center Houston
Department
Biology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225