Our laboratory is interested in the function of small G proteins in the cardiovascular system. We use transgenic mouse and zebrafish models for in vivo studies and a variety of biochemical, molecular and microscopy approaches to interrogate signaling by small GTPases in vascular cells ex vivo.
Small G protein Rap1 has been the main focus of our research over the past few years. Rap1, evolutionarily conserved and ubiquitously expressed, is activated downstream from multiple cell surface receptors and regulates several basic cellular functions: adhesion, migration, polarity, differentiation and growth. Well studied in vitro, Rap1 functions in mammalian systems in vivo are still not very well understood.
Using Rap1b-knockout mice we have recently revealed a novel role of Rap1bin vivo: regulation of angiogenesis. In an in vivo neonatal retinal model and a Matrigel plug model we demonstrated that Rap1b-deficiency leads to a defect in angiogenesis, and through ex vivo and in vitro studies, we localized the defect to endothelial cells and shown that endothelial proliferation and migration are affected by Rap1b-deficiency. At the molecular level, the underlying mechanism involves defective activation and signaling downstream from Vascular Endothelial Growth Factor (VEGF) Receptor 2. Current research in the laboratory is focused on elucidating molecular mechanisms through which Rap1 regulates endothelial cell responses to VEGF promoting angiogenesis.
Cardiac hypertrophy and hypertension
In addition to promoting angiogenesis, our studies indicate that Rap1b is required for maintenance of normal blood pressure as Rap1b-knockout mice are hypertensive and develop cardiac hypertrophy. This is a novel function of Rap1 and we are currently utilizing tissue-specific knockout mice to understand which physiological processes involved in regulation of blood pressure and normal cardiac function are regulated by Rap1.
Selected Resent Publications
Chrzanowska-Wodnicka M., Smyth S., Schoenwaelder SM, White GC. Rap1b is required for normal platelet function and hemostasis in mice. J Clin Invest 2005; 115: 680-7.
Chrzanowska-Wodnicka, M., White, G.C., Kraus, A.E. and VanSluys, J. “Defective angiogenesis, endothelial migration and MAPK signaling in Rap1b-/- mice”. – Blood 111:2647-56, 2008 (with “Inside Blood“commentary).
Chrzanowska-Wodnicka M. Regulation of angiogenesis by a small GTPase Rap1. Vascular Pharmacology 53:1-10, 2010.
Sobczak M, Dargatz J, Chrzanowska-Wodnicka M. Isolation and culture of murine microvascular endothelial cells. Journal of Visualized Experiments
Lakshmikanthan S, Sobczak M, Chun CZ, Henschel A, Dargatz J, Ramchandran R, Chrzanowska-Wodnicka M. Rap1 regulates angiogenesis by a mechanism involving integrin αvβ3-dependent VEGFR2 activation.” Blood, 10.1182/blood-2011-04-349282, 2011.