Role of PTEN in Hypoxia-Induced Vascular Remodeling, Raphael Nemenoff

PTEN 在缺氧诱导的血管重塑中的作用，Raphael Nemenoff

• 批准号: 7662790
• 负责人: Mary Cm. Weiser-Evans
• 金额: $ 32.14万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662790
• 关键词: 1-Phosphatidylinositol 3-Kinase; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Biological; Blood Vessels; Bone Marrow; CCL2 gene; CD14 gene; CXCR4 gene; Cell Proliferation; Cell Wall; Cells; Chronic; Data; Development; Exhibits; Fibroblasts; Growth; Heart failure; Homing; Hyperplasia; Hypoxia; In Vitro; Inflammatory; Inflammatory Response; Instruction; Interleukin-6; Knockout Mice; Laboratories; Lung; Maps; Medial; Mediating; Mediator of activation protein; Methodology; Modeling; Molecular; Mus; Muscle function; Mutant Strains Mice; Myosin Heavy Chains; Nuclear Receptors; PTEN gene; PTPRC gene; Pathogenesis; Pathology; Pathway interactions; Pioglitazone; Prevention; Principal Investigator; Process; Production; Prostaglandins I; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Regulation; Relative (related person); Research Personnel; Role; Serum; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myosins; Stem cells; Stromal Cell-Derived Factor 1; System; Tamoxifen; Testing; Therapeutic Agents; Time; Transgenic Mice; Up-Regulation; Vascular remodeling; Wild Type Mouse; Work; analog; autocrine; base; cell type; chemokine; cytokine; design; human FRAP1 protein; in vivo; inhibitor/antagonist; mouse model; novel; novel therapeutics; progenitor; protective effect; pulmonary arterial hypertension; research study; response; rosiglitazone; small hairpin RNA; spatiotemporal; trafficking; vasoconstriction

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. Aiml 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. RELEVANCE (See instructions): 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.

缺氧所致肺动脉高压（PAH）的发病机制具有以下特点