This application seeks renewal of a program that is now in its 35th year. The proposal comprises four scientific projects focused on studies of the mechanisms of hypoxic pulmonary hypertension (PH). The proposed studies are collectively founded on the hypothesis that the pathogenesis of hypoxic PH involves both functional (vasoconstriction and wall stiffening) and structural (vascular wall thickening) components, and that both components involve hypoxia-induced alterations in resident cell function as well as recruitment and interactions with inflammatory and/or progenitor cells. Projects 1, and 3 represent continuation and evolution of current program projects, while Projects 2 and 4 have been added to incorporate complementary new directions and expertise. The projects are highly interactive, both conceptually and in the performance and communication of experimental results, share numerous models and techniques, and are supported by three strong cores: administrative, animal, and tissue. The project leaders, Drs. Stenmark, Nemenoff, Klemm and Geraci have worked together on studies regarding cell signalling and of pulmonary hypertension for many years. The four projects address new and innovative hypotheses regarding the cellular mechanisms of chronic hypoxic PH. Project 1 explores the role of circulating myeloid mesenchymal progenitor cells, fibrocytes, in vascular remodeling and stiffening. Project 2 proposes that the phosphatase PTEN is a potent, endogenously produced inhibitor of SM proliferation and that SM-specific PTEN inactivation is an early and critical trigger driving vascular remodeling. Project 3 investigates how loss of CREB in SMC results in increases in SM proliferation, collagen elastin synthesis and VCAM-1 expression, which ultimately leads to accumulation of monocytes/progenitor cells and remodeling in the pulmonary arterial wall. Project 4 examines the role of disrupted PGI2 and PPAR? signaling in the aberrent cell growth characterizing chronic pulmonary vascular remodeling. These studies will provide new insights into the cellular/molecular mechanisms of chronic hypoxic pulmonary vasoconstriction and vascular stiffening and remodeling and may lead to novel, more effective therapy for hypoxic PH.
Pulmonary hypertension (PH) complicates the clinical course of many chronic heart and lung diseases. Its'presence significantly increases the morbidity and mortality of the underlying disease. Current treatments are non-specific and often unsuccessful because mechanisms leading to the development of PH remain unclear. Our goal is to better understand the disease process, ultimately allowing for successful intervention.
|SchÃ¤fer, Michal; Myers, Cynthia; Brown, R Dale et al. (2016) Pulmonary Arterial Stiffness: Toward a New Paradigm in Pulmonary Arterial Hypertension Pathophysiology and Assessment. Curr Hypertens Rep 18:4|
|Bartels, Karsten; Brown, R Dale; Fox, Daniel L et al. (2016) Right Ventricular Longitudinal Strain Is Depressed in a Bovine Model of Pulmonary Hypertension. Anesth Analg 122:1280-6|
|Voelkel, Norbert F; Tamosiuniene, Rasa; Nicolls, Mark R (2016) Challenges and opportunities in treating inflammation associated with pulmonary hypertension. Expert Rev Cardiovasc Ther 14:939-51|
|Graham, Brian B; Robinson, Jeffrey C; Tuder, Rubin M (2016) Fatty Acid Metabolism, Bone Morphogenetic Protein Receptor Type 2, and the Right Ventricle. Am J Respir Crit Care Med 194:655-6|
|Horita, Henrick; Wysoczynski, Christina L; Walker, Lori A et al. (2016) Nuclear PTEN functions as an essential regulator of SRF-dependent transcription to control smooth muscle differentiation. Nat Commun 7:10830|
|PlecitÃ¡-HlavatÃ¡, Lydie; Tauber, Jan; Li, Min et al. (2016) Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension. Am J Respir Cell Mol Biol 55:47-57|
|Keller, Amy C; Knaub, Leslie A; McClatchey, P Mason et al. (2016) Differential Mitochondrial Adaptation in Primary Vascular Smooth Muscle Cells from a Diabetic Rat Model. Oxid Med Cell Longev 2016:8524267|
|Stenmark, Kurt R; Frid, Maria; Perros, FrÃ©dÃ©ric (2016) Endothelial-to-Mesenchymal Transition: An Evolving Paradigm and a Promising Therapeutic Target in PAH. Circulation 133:1734-7|
|McClatchey, P Mason; Keller, Amy C; Bouchard, Ron et al. (2016) Fully automated software for quantitative measurements of mitochondrial morphology. Mitochondrion 26:58-71|
|Bruns, Danielle R; Buttrick, Peter M; Walker, Lori A (2016) Genetic ablation of interleukin-18 does not attenuate hypobaric hypoxia-induced right ventricular hypertrophy. Am J Physiol Lung Cell Mol Physiol 310:L542-50|
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