Heritable Pulmonary Arterial Hypertension (HPAH) is a rare, fatal disease of the pulmonary vasculature for which there is no cure. The majority of HPAH patients inherit mutations in the BMP type 2-receptor gene, BMPR2, but how these promote pulmonary vascular disease is unclear. In this work, we show BMPR2 mutations promote Src-kinase activation pulmonary endothelial cells (PECs) isolated from Bmpr2 mutant mice. We show increased Src activation leads to endothelial barrier defects due in part to enhanced Src-mediated caveolar endocytosis and that these defects can be rescued using Src kinase inhibitors. We go on to show that pulmonary endothelial cells and late outgrowth endothelial progenitor cells isolated from idiopathic PAH patients show similar increases in Src kinase activation suggesting that Src kinase activation may be a common disease mechanism in PAH. Therefor, these studies provide evidence for the use of Src kinase inhibitors in the treatment of pulmonary arterial hypertension.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-07062015-155323 |
| Date | 07 July 2015 |
| Creators | Prewitt, Allison Renee |
| Contributors | David Harrison, Anne Kenworthy, Mark de Caestecker, Matthew Tyska, Ethan Lee |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-07062015-155323/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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