Regulation of mural cells during pulmonary capillary formation

肺毛细血管形成过程中壁细胞的调节

• 批准号: 8195607
• 负责人: STEPHEN E MCGOWAN
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195607
• 关键词: Address; Adherens Junction; Adult; Alveolar; Alveolar Cell; Animal Model; Apoptosis; Area; Attenuated; Basement membrane; Birth; Blood Cells; Blood Vessels; Blood capillaries; Blood flow; Brain; Bronchopulmonary Dysplasia; Cadherins; Cell Adhesion Molecules; Cell Communication; Cell Maintenance; Cell surface; Cells; Characteristics; Chronic Kidney Insufficiency; Chronic Obstructive Airway Disease; Defect; Development; Diabetes Mellitus; Diffusion; Disease; Disease Progression; Endothelial Cells; Endothelium; Ensure; Epithelial Cells; Extravasation; Fibroblasts; Fibrosis; Filtration; Fostering; Gap Junctions; Gases; Goals; Growth; Health Care Costs; Healthcare; Hospitalization; Human; In Vitro; Integrins; Kidney; LacZ Genes; Laminin; Laser Scanning Confocal Microscopy; Learning; Liver; Longevity; Lung; Mediating; Mesenchymal; Microcirculatory Bed; Microscopic; Molecular; Mus; Myofibroblast; Newborn Infant; Nuclear; Organ; Outcome; PDGF Signaling Pathway; Pathogenesis; Pericytes; Permeability; Phosphotransferases; Plasma; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor alpha Receptor; Population; Pulmonary Circulation; Pulmonary Emphysema; Pulmonary Gas Exchange; Pulmonary Hypertension; Regulation; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stroke; Structure; Supporting Cell; Surface; Symptoms; Therapeutic; Tight Junctions; Time; Tube; Vascular Diseases; Vascular Endothelial Growth Factors; Veterans; angiogenesis; arteriole; capillary; capillary bed; cell motility; cost; improved; interstitial; intimate behavior; mesangial cell; migration; mixed cell culture; nectin; neutrophil; novel; platelet-derived growth factor A; prevent; public health relevance; repaired; restoration; smoking prevalence; stellate cell; tumor; venule

PROJECT SUMMARY: The structure and function of alveolar capillaries are deranged in pulmonary emphysema. Restoration of the pulmonary microvasculature is also an important therapeutic goal for interstitial fibrosis and other causes of pulmonary hypertension. A critical step towards achieving this goal is to identify factors which regulate capillary expansion and maturation during alveolar septal formation. Hypothesis: Formation and expansion of the alveolar capillary network requires cooperation among endothelial cells, pericytes, and lung fibroblasts (LF). During secondary septal formation, PDGF-mediated signaling directs pericytes and MF to ensure (a) expansion and maintenance of these cell populations, (b) migration and establishment of intercellular contacts with the endothelium, and (c) sub-division of the existing endothelial tubes to allow rapid expansion of capillary surface area. Specific Aim 1: To (a) demonstrate that fibroblasts and pericytes spatially converge on the endothelium as the capillary meshwork forms during septation and (b) investigate how PDGF-mediated signaling regulates formation of the mural sheath by pericytes and myofibroblasts in mice. Specific Aim 2: Examine cellular mechanisms whereby PDGF-A and PDGF-B promote formation of the mural sheath in vitro by enhancing cell migration and the formation of cell- cell contacts along endothelial tubes. Genetically modified mice will be used to identify and localize alveolar cells which (a) express PDGF receptor-alpha (PDGF-R¿) or (b) have characteristics of pericytes. Laser scanning confocal microscopy (LSCM) and stereology will be used to analyze ingress of LF and pericytes and their association with alveolar endothelial cells in the meshwork. These studies will ascertain if there is a temporally progressive decrease in the distance between the capillary endothelium and surrounding LF and pericytes. Studies will also examine how disrupting PDGF-signaling pathways in LF and pericytes alters (a) the capillary meshwork and (b) pericyte and LF proliferation and longevity. Important signaling pathways, which are initiated by PDGFs, are mediated by Abelson kinase and Rac1, and alter pericyte or LF proliferation and apoptosis will be examined. The second aim we will examine how PDGF-A and PDGF-B direct the migration and association of endothelial cells, LF, and pericytes in culture. Endothelial and mural cells coalesce in the capillary wall. To learn how these cells intermingle, cell surface adhesion molecules will be compared when mural cells migrate to when the mural coalesce with the endothelial basement membrane. Molecules, including nectins and cadherins, which regulate cell-cell interactions will be investigated as cells transition from a migratory to a sessile state, and form adherens and tight junctions. Detailed time-lapse microscopic studies will reveal how laminin and integrins promote PDGF-A or PDGF-B-stimulated migration of fibroblasts and pericytes. These studies will provide novel information about non-sprouting angiogenesis (NSA) in the lung. A better understanding of NSA may identify factors that are also important in the pathogenesis and repair of diseases involving other microvascular beds such as the kidneys and brain. Microangiopathies are central to diabetes, stroke, and chronic renal insufficiency, which are becoming more prevalent among veterans. . Potential impact for veterans' health care: These studies may foster the development of new therapies resulting in improved outcomes and lower costs for treating pulmonary emphysema and vascular diseases, which is are common among veterans.

项目摘要：肺泡毛细血管的结构和功能紊乱