Although it is known that the response of endothelial cells to atherogenic disturbed flow is distinct from that elicited by non-atherogenic laminar flow, the mechanisms involved are poorly understood. Observing that expression of the endothelial receptor tyrosine kinase, Tie1, is evident only at regions of atherogenic flow in mature animals, we hypothesized that Tie1 plays a role in the endothelial response to atherogenic shear stress. Because deletion of Tie1 results in embryonic lethality secondary to vascular dysfunction, we utilized conditional and inducible mutagenesis (Tie1-/flox:SCL-ERT-Cre) to study the effect of Tie1 attenuation on atherogenesis in apolipoprotein E deficient (ApoE-/-) mice, and found a dose dependent decrease (70%) in atherosclerotic lesions. To test our hypothesis, we isolated primary aortic endothelial cells from Tie1flox/flox:SCL-ERT-Cre immorto mice and found that atheroprotective laminar flow decreased Tie1 expression in vitro. Attenuation of Tie1 was associated with an increase in eNOS expression and Tie2 phosphorylation, In addition, Tie1 attenuation increased IkB-α expression while attenuating. In summary, we found that shear stress conditions that modulate atherogenic events also regulate Tie1 expression and Tie1 may play a novel pro-inflammatory role in atherosclerosis.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-06182010-135732 |
| Date | 12 July 2010 |
| Creators | Woo, Kel Vin |
| Contributors | Steve Hanks, H. Scott Baldwin, Sergio Fazio, Raul Guzman, Charles Lin, Matt Tyska |
| 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-06182010-135732/ |
| 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. |
Page generated in 0.0196 seconds