Vascular remodeling in pulmonary arterial hypertension (PHTN) is a heterogeneous disorder which varies depending upon the type of injury, suggesting that smooth muscle cells within a vessel wall respond in distinct ways to different stimuli. Our preliminary data suggests that the medial thickening and vascular remodeling associated with PHTN does not result from a uniform proliferation of all smooth muscle cells within the pulmonary vessel, but from selective activation of subsets of pulmonary artery smooth muscle cells (PA SMC). Since the cause of PHTN can vary between individuals, understanding how subtypes of PA SMC respond to different types of injury has potential therapeutic implication. We hypothesize that subsets of PA SMC, identified by their ability to escape G0/G1 arrest following vascular injury, are responsible for the vessel remodeling in PHTN. Using cell culture, organ culture of extra-lobar and resistance pulmonary vessels, and in vivo experiments from both wild type and cyclin-dependent kinase inhibitor- (p21Cip1/Waf1 and p27Kip1) deficient animals we will examine: 1) how G1 cell cycle proteins are regulated in 'proliferative' compared to 'non-proliferative' PA SMC following stimulation, 2) the role of 3 intracellular signaling pathways which target G1 cell cycle proteins (RhoA/Rho kinase, P(3) kinase/AKT, and CREB) on regulating PA SMC proliferation within these subtypes, and 3) the effectiveness of three clinically relevant therapies (prostacyclin, endothelin blockers, and HMG CoA reductase inhibitors (statins)) in controlling proliferation in these subset(s) of PA SMC following injury. We anticipate that at the conclusion of this proposal we will have identified how subsets of PA SMC are selectively induced to proliferate in response to vascular injury. This information may lead to more targeted therapy for the treatment of PHTN.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070273-03
Application #
7076921
Study Section
Respiratory Physiology Study Section (RESP)
Program Officer
Denholm, Elizabeth M
Project Start
2004-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$356,423
Indirect Cost
Name
University of South Alabama
Department
Biology
Type
Schools of Medicine
DUNS #
172750234
City
Mobile
State
AL
Country
United States
Zip Code
36688
Solodushko, Victor; Khader, Heba A; Fouty, Brian W (2013) Serum can overcome contact inhibition in confluent human pulmonary artery smooth muscle cells. PLoS One 8:e71490
Solodushko, Victor; Alvarez, Diego F; Viator, Ryan et al. (2011) Heterogeneous activation of p19Arf in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 300:L642-7
Solodushko, V; Fouty, B (2010) Mifepristone increases gamma-retroviral infection efficiency by enhancing the integration of virus into the genome of infected cells. Gene Ther 17:1253-61
Solodushko, Victor; Bitko, Vira; Fouty, Brian (2009) Dexamethasone and mifepristone increase retroviral infectivity through different mechanisms. Am J Physiol Lung Cell Mol Physiol 297:L538-45
Solodushko, Victor; Parker, James C; Fouty, Brian (2008) Pulmonary microvascular endothelial cells form a tighter monolayer when grown in chronic hypoxia. Am J Respir Cell Mol Biol 38:491-7
Fouty, Brian (2008) Diabetes and the pulmonary circulation. Am J Physiol Lung Cell Mol Physiol 295:L725-6
Solodushko, Victor; Fouty, Brian (2007) Proproliferative phenotype of pulmonary microvascular endothelial cells. Am J Physiol Lung Cell Mol Physiol 292:L671-7
Fouty, B; Moss, T; Solodushko, V et al. (2006) Dexamethasone can stimulate G1-S phase transition in human airway fibroblasts in asthma. Eur Respir J 27:1160-7