The molecular mechanisms underlying formation of occlusive vascular lesions in pulmonary arterial hypertension (PAH) are unknown. PASMCs in the normal vasculature exhibit a differentiated, contractile, non-proliferative phenotype. During the development of PAH, the PASMCs dedifferentiate and become hyperproliferative and migratory leading to neointimal occlusion of small pulmonary arteries and arterioles. Although several signaling molecules have been investigated, it remains unclear what the vascular signals are that cause this dedifferentiation and neointimal lesion formation. Crosstalk between PAECs and PASMCs has long been suspected to participate in pathogenesis of PAH. Further, our data suggest direct interactions between PAECs and PASMCs through myoendothelial gap junctions are important for maintenance of the normal differentiated PASMC phenotype. Injury or alterations to the PAEC monolayer affect the differentiation status of the adjoining PASMCs. Not only do PASMCs and PAECs communicate with each other, but PAECs are also exposed to numerous circulating factors. Microparticles (MPs) are circulating intact vesicles which function as regulators of vascular homeostasis, cell proliferation, and angiogenesis;all vital processes in PAH occlusive vascular lesion formation. Based on these observations this proposal tests the overall hypothesis that aberrant myoendothelial gap junctional signaling between PAECs and PASMCs contributes to the arteriopathy of PAH by promoting dedifferentiation and proliferation of PASMCs, and that MPs from PAH patients participate in the pathogenesis of the vascular disease by inducing PAEC dysfunction and disrupting the gap junctional signaling.
Specific Aims test the hypotheses that:
Aim 1 : Aberrant gap junctional signaling between PAH PAECs and PASMCs promotes PASMC dedifferentiation and proliferation.
Aim 2 : Circulating MPs isolated from PAH patients cause PAEC dysfunction and disrupt myoendothelial gap junctional signaling, which leads to dedifferentiation and proliferation of co-cultured PASMCs.

Public Health Relevance

Pulmonary arterial hypertension (PAH) is a devastating disease for which there is currently limited treatment and no cure. This disease is characterized by lesion formation in the pulmonary vessels. From the studies in our proposal we hope to understand the process for lesion formation in the pulmonary vasculature in the hopes of developing new therapeutics for PAH.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Small Research Grants (R03)
Project #
1R03HL110828-01
Application #
8211913
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (S1))
Program Officer
Moore, Timothy M
Project Start
2011-09-23
Project End
2013-07-31
Budget Start
2011-09-23
Budget End
2012-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$74,250
Indirect Cost
Name
University of South Alabama
Department
Pharmacology
Type
Schools of Medicine
DUNS #
172750234
City
Mobile
State
AL
Country
United States
Zip Code
36688