Associate Professor, Surgery
Membership effective July 2008
Genetic programming and hemodynamic signal transduction in vascular development and disease
Blood vessel regeneration is critical for cardiovascular disease, cancer, and tissue regeneration, and formation of arterial venous hierarchy is a major challenge in this area of research. The long-term interest of my laboratory is to elucidate the molecular regulators and the cellular processes involved in arterial venous specification in the endothelial cells lining the vascular lumen. We study these questions through a combined approach including mouse genetics, in vivo imaging, and computational analysis of hemodynamics.
While both hemodynamic and genetic forces control arterial venous specification, the biochemical basis of this mechanotransduction and the cellular mechanism of the genetic regulation are largely unknown. One focus of my lab is to elucidate how hemodynamic effects are translated into biochemical cues that regulate artery formation. This project and our discovery of molecules that promote arterial formation have important bearing on the engineering of artery grafts. Another focus of the lab is on cell signaling in the pathogenesis of brain arteriovenous malformation. We have established that activation of a receptor called Notch leads to prompt brain arteriovenous malformation in mice, offering both a molecular cue and a faithful animal model with which to study the molecular etiology of this disease.
The ability to accurately and quantitatively measure both vessel structure and blood flow is crucial in our studies. We have recently completed the construction of a two-photon excited fluorescence microscope optimized for measuring blood flow and mapping vascular topology. This innovative technology allows us to achieve unprecedented resolution of vascular structure and function in the living animal. Our work may unravel signaling cascades regulating arterial specification and facilitate the engineering of artery replacement.
TR Carlson, Y Yan, X Wu, MT Lam, GL Tang, LJ Beverly, LM Messina, AJ Capobianco, Z Werb and R Wang. Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Proc Natl Acad Sci U S A, 2005 102(28): 9884-9.
TR Carlson, H Hu, R Braren, YH Kim, and RA Wang. Cell-autonomous requirement for β1 integrin in endothelial cell adhesion, migration, and survival during angiogenesis in mice. Development, 2008 135(12):2193-202.
C He, H Hu, R Braren, S-Y Fong, A Trumpp, TR Carlson, and RA Wang. c-myc in the hematopoetic lineage is crucial for its angiogenic function in the mouse embryo. Development, 2008 135(14):2467-77.
Murphy, PA, MTY Lam, X Wu, TN Kim, SM Vartanian, AW Bollen, TR Carlson, and RA Wang. Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice. Proc Natl Acad Sci U S A, 2008 105(31):10901-10906.
Kim, YH, H Hu, S Guevara-Gallardo, MTY Lam, S-Y Fong, and RA Wang. Artery and vein size is balanced by Notch and ephrinB2/EphB4 during angiogenesis. Development, 2008 135(22):3755-3764.
Murphy, PA, G Lu, S Shiah, AW Bollen, and RA Wang. Endothelial Notch signaling is upregulated in human brain arteriovenous malformations and a mouse model of the disease. Lab Invest, 2009 89(9):971-82.