Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries marked by a progressive increase in pulmonary vascular resistance, leading to right heart failure and ultimately death. An imbalance between vasoconstriction and vasodilation coupled with vascular remodeling and overgrowth are hallmarks of PAH. Nitric oxide (NO) is known to play a protective role in PAH and endothelial failure and loss of NO signaling contribute to both human and experimental PAH. Recent work by the principal investigator has found that the matrix protein thrombospondin-1 (TSP1) blocks physiologic NO responses in vascular cells. Preliminary data suggests that TSP1, in binding to its necessary receptor CD47, inhibits activation of endothelial nitric oxide synthase (eNOS) and thus endothelial NO production, and that TSP1 and CD47 are dramatically upregulated in human and experimental PAH. Additional new data demonstrates that the TSP1-CD47 nexus stimulates vascular smooth muscle cell overgrowth in a PDGF-dependent manner in PAH. The central hypothesis to be tested in this proposal is that excessive TSP1 expression underlies PAH vasculopathy and that interaction with its cognate receptor, CD47, selectively regulates key second messenger pathways linked to microvascular vasoreactivity, growth, and remodeling. The present proposal will explore (i) the mechanisms behind upregulation of TSP1-CD47 in PAH, (ii) the implications this has on vascular tone and overgrowth and (iii) the effects that therapeutic interruption of the nexus has on preventing PAH and on ameliorating established disease.

Public Health Relevance

Pulmonary arterial hypertension (PAH) is a progressive disease that can occur without an identifiable cause or as a consequence of a number of chronic diseases of the lung, heart and liver. In all instances the disease leads to changes in lung function and blood flow that ultimately results in heart failure and death. There are no known cures and available therapy does little to stem the process or extend life. Central to the pathogenesis of PAH is concurrent changes in lung blood vessels that block flow from concurrent increased arterial constriction and thickening of smooth muscle cell layers in small pulmonary arteries. Nitric oxide (NO) is a natural biogas that promotes blood flow and vasodilation in pulmonary blood vessels. Loss of NO signaling is found in PAH and currently useful therapies target NO and try to increase this agent in the lung. Another central mediator of PAH is the smooth muscle cell growth factor platelet derived growth factor (PDGF). We have discovered a novel ligand-receptor interaction between thrombospondin-1 and CD47 that serves as a master regulator of both NO and PDGF. We have also found dramatic upregulation of the TSP1-CD47 nexus in human and several experimental models of PAH. Therapeutics that target the TSP1-CD47 pathway maximize NO and increase blood flow while simultaneously inhibiting smooth muscle cell hypertrophy and arterial thickening. In this proposal we will test the hypothesis that TSP1 promotes PAH through multiple pathways and that blocking TSP1 will both prevent and ameliorate PAH.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL108954-02
Application #
8294522
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Moore, Timothy M
Project Start
2011-07-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$319,577
Indirect Cost
$108,635
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Labrousse-Arias, David; Castillo-González, Raquel; Rogers, Natasha M et al. (2016) HIF-2α-mediated induction of pulmonary thrombospondin-1 contributes to hypoxia-driven vascular remodelling and vasoconstriction. Cardiovasc Res 109:115-30
Procter, Nathan Ek; Ball, Jocasta; Ngo, Doan Tm et al. (2016) Gender and tachycardia: independent modulation of platelet reactivity in patients with atrial fibrillation. J Geriatr Cardiol 13:202-8
Rogers, Natasha M; Isenberg, Jeffrey S (2015) Seeing is believing: NO therapy for glaucoma? Focus on "Role of nitric oxide in murine conventional outflow physiology". Am J Physiol Cell Physiol 309:C203-4
Procter, Nathan E K; Ball, Jocasta; Liu, Saifei et al. (2015) Impaired platelet nitric oxide response in patients with new onset atrial fibrillation. Int J Cardiol 179:160-5
Kutten, Johannes C; McGovern, David; Hobson, Christopher M et al. (2015) Decellularized tracheal extracellular matrix supports epithelial migration, differentiation, and function. Tissue Eng Part A 21:75-84
Rogers, Natasha M; Isenberg, Jeffrey S (2014) Endothelial cell global positioning system for pulmonary arterial hypertension: homing in on vascular repair. Arterioscler Thromb Vasc Biol 34:1336-8
Rogers, Natasha M; Ferenbach, David A; Isenberg, Jeffrey S et al. (2014) Dendritic cells and macrophages in the kidney: a spectrum of good and evil. Nat Rev Nephrol 10:625-43
Soto-Pantoja, David R; Shih, Hubert B; Maxhimer, Justin B et al. (2014) Thrombospondin-1 and CD47 signaling regulate healing of thermal injury in mice. Matrix Biol 37:25-34
Yao, Mingyi; Rogers, Natasha M; Csányi, Gábor et al. (2014) Thrombospondin-1 activation of signal-regulatory protein-α stimulates reactive oxygen species production and promotes renal ischemia reperfusion injury. J Am Soc Nephrol 25:1171-86
Rogers, Natasha M; Sharifi-Sanjani, Maryam; Csányi, Gábor et al. (2014) Thrombospondin-1 and CD47 regulation of cardiac, pulmonary and vascular responses in health and disease. Matrix Biol 37:92-101

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