(Verbatim from the application): All organs of the body are absolutely dependent on the ability of the cardiovascular system to pump blood through blood vessels for distributing oxygen, nutrients, hormones and other factors to the tissues. The dynamic forces emanating from the circulating blood can have significant deleterious effects, even contributing to many vascular diseases including atherosclerosis, microangiopathies and hypertension. The endothelial cells lining blood vessels are directly exposed to the mechanical stresses from the flow and normally respond rapidly to compensate for stress changes, for example by releasing vasoactive molecules or expressing atheroprotective genes. How they initiate this protective function is unknown. This grant focuses on molecular mechanisms mediating the initial aspects of the acute endothelial response by looking specifically at the endothelial cell surface immediately exposed to the hemodynamic forces. Our hypothesis is that the endothelial cell surface mediates acute mechanotransduction via specific cell surface microdomains called caveolae that act as mechanosensing organelles.
Our specific aims are: 1) to define the role of the endothelial cell surface and its caveolae in part through the characterization of our novel model systems for analyzing the effects of mechanical stress on various endothelial cells in tissues, in culture and in reconstituted membrane subfractions; 2) to determine the role of caveolin in sensing mechanical stress and activating downstream signaling molecules; and 3) to define the function of heterotrimeric G proteins in mechanotransduction with emphasis on how Gaq interacts with caveolin to mediate mechano-signaling by endothelium. We will utilize pharmacological inhibitors as well as the expression of mutant recombinant proteins to dissect mechanotransduction. By understanding the role of the endothelial cell surface and its caveolae in stress adaptation, we may gain new insights in the etiology of major vascular diseases and ultimately understand how to prevent deleterious events in order to prevent the disease or find new avenues of treatment.
| Oh, Phil; Horner, Thierry; Witkiewicz, Halina et al. (2012) Endothelin induces rapid, dynamin-mediated budding of endothelial caveolae rich in ET-B. J Biol Chem 287:17353-62 |
| Chrastina, Adrian; Massey, Kerri A; Schnitzer, Jan E (2011) Overcoming in vivo barriers to targeted nanodelivery. Wiley Interdiscip Rev Nanomed Nanobiotechnol 3:421-37 |
| Czarny, Malgorzata; Liu, Jun; Oh, Phil et al. (2003) Transient mechanoactivation of neutral sphingomyelinase in caveolae to generate ceramide. J Biol Chem 278:4424-30 |
