Research Overview
Cardiovascular Development
Cardiovascular Genetics and Development. Research in our lab focuses on understanding the mechanisms of early events in cardiovascular development. This is an important area of research, since errors in embryonic cardiovascular development are the most common causes of congenital birth defects in humans. During embryogenesis, cardiovascular system composed of blood vessels and the heart, is assembled from precursor cells originating in various embryonic locations. Migration of these precursor cells from their embryonic origins to the sites of forming heart and blood vessels is a pivotal step in organ formation. How this process happens is not well understood. We use mouse as a model organism to study the molecules essential for this process and to identify new factors guiding cardiac and vascular progenitors to their embryonic destinations. Heart Development. Heart is the first organ to form in a vertebrate embryo and is initially composed of a tube assembled from two coalescing primordia migrating toward the embryonic midline from their positions on the left and on the right. One project in the lab is to identify new factors required for migration of precursor cells to from a heart tube. To this end, we have employed a genetic system wherein heart tube does not form in the absence of an extracellular matrix protein fibronectin in mice from 129S4 genetic background but does form in fibronectin-null mice from C57BL/6J genetic strain. We have located the position of a genetic difference between these two strains to a one-megabase interval on mouse chromosome four and identified genes that are differentially expressed between the strains. We are now in the process of determining which of these differentially expressed genes accounts for the difference in heart formation in fibronectin-null embryos derived from 129S4 and C57BL/6J genetic backgrounds. Other projects in the lab address the role of fibronectin and its cellular receptor integrin α5β1 in heart development, in particular, in the recruitment of cardiac progenitor cells from various embryonic origins into the heart. Our long-term goal is to identify novel factors regulating recruitment of cardiac progenitor cells into the heart. Astrof S, Kirby A, Lindblad-Toh K, Daly M, Hynes RO. Heart development in fibronectin-null mice is governed by a genetic modifier on chromosome four. Mech Dev. 2007 Aug; 124(7-8): 551-8. Vascular Biology. New blood vessel formation is equally crucial for both the development of a vertebrate organism and for tumor growth. Vasculature is necessary to provide oxygen and nutrients to a developing embryo or a tumor mass; without vascular supply, embryos fail to survive and tumors fail to grow beyond 1.5 mm in diameter. During vessel development both in embryos and in tumors, blood vessel endothelial cells recruit and associate with perivascular cells called pericytes or vascular smooth muscle cells (VSMCs). This association is necessary for the survival and proper function of vessels in both embryos and tumors. Normal and tumor vessels regress when association between endothelial cells and pericytes is blocked In order to design effective therapies to inhibit new blood vessel growth during pathological processes including tumorigenesis, atherosclerosis, and diabetic retinopathy we need to understand how VSMCs form. The development of VSMC layer around blood vessels is a multistep process during which progenitors of pericytes/VSMCs need to migrate toward blood vessels from their place(s) of origin, differentiate, associate with vessels and spread along the vessel wall. In order to understand the mechanism of recruitment of VSMCs to blood vessels, we generated double-knock out mice in which two alternatively spliced exons of fibronectin were deleted. These alternatively spliced exons, called EIIIA and EIIIB are highly conserved in evolution and have been hypothesized to function in vascular development. Our studies indicated that the absence of both of the EIIIA and EIIIB exons caused severe cardiovascular defects and was embryonic lethal. We also showed a decrease in the number of VSMCs around the paired embryonic dorsal aortae. We are now investigating the role of EIIIA and EIIIB splice variants of fibronectin in the recruitment of VSMC precursor cells to dorsal aortae and to other embryonic vessels. Astrof S, Crowley D, Hynes RO. Multiple cardiovascular defects caused by the absence of alternatively spliced segments of fibronectin. Dev Biol. 2007 Oct; 311:11-24. For more information, please visit the Weill Cornell Cardiology website.
