Patricia D'Amore
The Schepens Eye Research Institute
3rd Floor
20 Staniford Street- 2 West
Boston, MA 02114
Tel: 617-912-2559
Fax: 617-912-0128
Email: patricia_damore@meei.harvard.edu
Lab Members: 4 postdoctoral fellows, 3 graduate students
Visit my lab page here.
The D’Amore laboratory is interested in understanding the regulation of vascular development during embryogenesis and subsequent growth control in the adult. Cellular and genetic approaches are used to investigate the mechanisms that control vessel formation and stability.
Vascular endothelial growth factor (VEGF) is critical for vasculogenesis and for angiogenesis in both normal and pathologic conditions, and is synthesized by alternative splicing as at least three isoforms (VEGF120, VEGF164, and VEGF188). The variable affinity of the isoforms for heparan sulfate proteoglycan and their differential binding to neuropilin, a VEGF co-receptor, led us to hypothesize that the isoforms might serve specific functions. Quantitative RNAse protection revealed that the relative levels of individual isoforms vary during organ development and in adult organs, an observation consistent with the concept that the isoforms might have distinct roles. We generated mice that express single isoforms and have found they have very distinct phenotypes. Current studies are revealing that the isoforms produced by each tissue reflect the relationship between VEGF-producing cells and the microvasculature.
The persistent expression of VEGF in virtually all adult tissues in the absence of active angiogenesis suggests an alternative function for VEGF. We hypothesize that VEGF plays a role as a survival factor for both vascular cells and non-vascular cells. To test this hypothesis, we are: 1) generating mice that can be induced to express dominant negative VEGFR2 specifically in the endothelium, allowing us to test the role of VEGF in the adult vasculature; and, 2) expressing a soluble VEGF receptor using an adenovirus. We have found that systemic VEGF neutralization leads to vessel non-perfusion in several organs that is accompanied by the presence of microthrombi and significant tissue dysfunction. We have also identified a number of novel non-vascular cell targets, including cells of the lens and neural retina. These results have profound implications for the current widespread use of anti-VEGF therapies in cancer and in wet macular degeneration.
Cell-cell interactions also play a role in vessel development and function. Using tissue culture models in which we coculture endothelial cells (EC) and pericytes/smooth muscle cells (or their precursors), we have shown that EC influence the migration and proliferation as well as differentiation of pericytes via PDGF B and TGF-ß, respectively. Association between EC and pericytes appear to stabilize vessel structures in vivo and we have reproduced this phenomenon in a three-dimensional coculture model. Current studies are aimed at investigating the cellular and molecular bases for the regulation of vascular cell differentiation and vessel stabilization.
References:
Coordinated vascular endothelial growth factor expression and signaling during skeletal myogenic differentiation. Bryan BA, Walshe TE, Mitchell DC, Havumaki JS, Saint-Geniez M, Maharaj AS, Maldonado AE, D'Amore PA. Mol Biol Cell. 2008 Mar;19(3):994-1006. Epub 2007 Dec 19.
Inhibition of VEGF or TGF-{beta} Signaling Activates Endothelium and Increases Leukocyte Rolling. Walshe TE, Dole VS, Maharaj AS, Patten IS, Wagner DD, D'Amore PA. Arterioscler Thromb Vasc Biol. 2009 May 21.
Endogenous VEGF is required for visual function: evidence for a survival role on müller cells and photoreceptors. Saint-Geniez M, Maharaj AS, Walshe TE, Tucker BA, Sekiyama E, Kurihara T, Darland DC, Young MJ, D'Amore PA. PLoS ONE. 2008;3(11):e3554. Epub 2008 Nov 3.
VEGF and TGF-beta are required for the maintenance of the choroid plexus and ependyma. Maharaj AS, Walshe TE, Saint-Geniez M, Venkatesha S, Maldonado AE, Himes NC, Matharu KS, Karumanchi SA, D'Amore PA. J Exp Med. 2008 Feb 18;205(2):491-501. Epub 2008 Feb 11.
Bryan BA, Dennstedt E , Mitchell DC, Walshe TE, Noma K, Loureiro R, Saint-Geniez M, Campaigniac J-P, Liao JK, D’Amore PA. RhoA/ROCK signaling is essential for multiple aspects of VEGF-mediated . FASEB J, 2010, April 6 Epub ahead of print, 10.1096/fj.09-145102.
For a complete listing of publications click here.
Last Update: 1/3/2013