The pathogenesis of hypoxia-induced pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling contributingto increased pulmonary vascular resistance leading to right heart failure. These responses are characterized by functional changes in resident vascular wall cells including smooth muscle (SMC), endothelial,and fibroblast, as well as recruitment of circulating progenitor and inflammatory cells. Our preliminary data indicatethat hypoxia leads to rapid activation of Akt in SMC of the lung vasculature. PTEN is a negative regulator of PI3-kinase/Akt/mTOR signaling, and an inhibitor of SMC proliferation. We have shown that SMC-specific, targeted PTEN mutant mice (PTEN KO) spontaneously develop pulmonary hypertension. PTEN KO mice also exhibit increased perivascular and serum chemokine levels, increases in circulating progenitor cells, and trafficking of progenitor cells to major vessels and the lung. Work by other investigators in this PPG demonstrated that rosiglitazone, a specific activator of the nuclear receptor PPARy, attenuates hypoxia-induced pulmonary vascular remodeling. In other systems, the ability of PPARy to inhibit cell proliferation and regulate anti-inflammatory responses is mediated, in large part, through the upregulation of PTEN expression and/or activity. Based on these collective observations, we hypothesize that inactivation of PTEN in pulmonary arterial SMC will induce severe PAH in response to chronic hypoxia. This response will be mediated by direct effects on SMC hyperplasia as well as the production of chemokines by SMC which will be involved in the recruitment of progenitor/pro-inflammatory cells and may also act in an autocrine fashion on the SMC themselves. Conversely, activation of PPARy will inhibit hypoxia-induced pulmonary vascular remodeling at least in part through the upregulation of PTEN. This project will employ both in vivo and in vitro approaches to test this model.
Two specific aims are proposed.
Aim l will use a novel, tampxifen-inducible PTEN knockout mouse model to examine the effects of SMC-specific deletion of PTEN in mice on chemokine- induced SMC hyperplasia and recruitment of progenitor and inflammatory cells during hypoxia-induced pulmonary vascular remodeling. This model will allow fate-mapping of medial SMC and bone marrow- derived progenitor cells during the pathogenesis of PAH, providing clear information regarding the contributions of these cells in pulmonary vascular remodeling. In vitro studies will use shRNA silencing of PTEN in pulmonary artery SMC to define downstream effectors mediating these responses.
Aim 2 will employ an analogous strategy to specifically delete PPARy in vivo and compare responses with PTEN deficient mice. In vitro experiments will establish the role of PTEN in mediating the effects of PPARy. Finally, the role of PTEN in mediating the protective effects of rosiglitazone and pioglitazone, two well- characterized PPARy activators, will be examined.
The molecular pathways mediating hypoxia-induced PAH involve multiple cell types. This project is designed to specifically examine the contribution of SMC to this process. Novel mouse models in which signaling pathways can be manipulated in a time-dependent fashion specifically in SMC will define the role of SMC. In vitro approaches will delineate molecular pathways controlling growth, phenotypic modulation and cytokine production by these cells. Pharmacological agents regulating these pathways represent novel therapeutic agents for treatment and prevention of PAH.
|Jiang, Xinguo; Nicolls, Mark R; Tian, Wen et al. (2018) Lymphatic Dysfunction, Leukotrienes, and Lymphedema. Annu Rev Physiol 80:49-70|
|Schäfer, Michal; Humphries, Stephen; Stenmark, Kurt R et al. (2018) 4D-flow cardiac magnetic resonance-derived vorticity is sensitive marker of left ventricular diastolic dysfunction in patients with mild-to-moderate chronic obstructive pulmonary disease. Eur Heart J Cardiovasc Imaging 19:415-424|
|D'Alessandro, Angelo; El Kasmi, Karim C; Plecitá-Hlavatá, Lydie et al. (2018) Hallmarks of Pulmonary Hypertension: Mesenchymal and Inflammatory Cell Metabolic Reprogramming. Antioxid Redox Signal 28:230-250|
|Karoor, Vijaya; Fini, Mehdi A; Loomis, Zoe et al. (2018) Sustained Activation of Rho GTPases Promotes a Synthetic Pulmonary Artery Smooth Muscle Cell Phenotype in Neprilysin Null Mice. Arterioscler Thromb Vasc Biol 38:154-163|
|Stenmark, Kurt R; Graham, Brian B (2018) Urocortin 2: will a drug targeting both the vasculature and the right ventricle be the future of pulmonary hypertension therapy? Cardiovasc Res 114:1057-1059|
|Madhavan, Krishna; Frid, Maria G; Hunter, Kendall et al. (2018) Development of an electrospun biomimetic polyurea scaffold suitable for vascular grafting. J Biomed Mater Res B Appl Biomater 106:278-290|
|Stenmark, Kurt R; Frid, Maria G; Graham, Brian B et al. (2018) Dynamic and diverse changes in the functional properties of vascular smooth muscle cells in pulmonary hypertension. Cardiovasc Res 114:551-564|
|Schäfer, Michal; Kheyfets, Vitaly O; Barker, Alex J et al. (2018) Reduced shear stress and associated aortic deformation in the thoracic aorta of patients with chronic obstructive pulmonary disease. J Vasc Surg 68:246-253|
|Graham, Brian B; Kumar, Rahul; Mickael, Claudia et al. (2018) Vascular Adaptation of the Right Ventricle in Experimental Pulmonary Hypertension. Am J Respir Cell Mol Biol 59:479-489|
|Wick, Marilee J; Harral, Julie W; Loomis, Zoe L et al. (2018) An Optimized Evans Blue Protocol to Assess Vascular Leak in the Mouse. J Vis Exp :|
Showing the most recent 10 out of 148 publications