The formation of blood vessels is a complex process that involves a coordinated temporal and spatial expression of a multitude of proteins. These proteins, which include signaling molecules, receptors, cytokines and structural components, ultimately determine the final architecture of the mature vessel from a single layered capillary to a multilayered aorta. For many years, elastic fibers present in blood vessel walls were thought to provide purely a structural and supportive function for the mature vessel. Recently, however, with the generation of an elastin knockout mouse, we have discovered that when no elastin is present in the blood vessel wall, the smooth muscle cells grow uncontrollably and proliferate so as to occlude the lumen of the vessel, causing death by 3 days of post-natal age. Since virtually nothing is known about how elastin influences vessel formation, one of our primary research objectives is to provide fundamental information concerning the role of elastin in vascular development and in smooth muscle cell differentiation. Ultimately, with this knowledge, we will be better able to understand the pathogenesis of vascular occlusive diseases and thus further expand our research efforts into the study and management of these diseases.
A second research focus of the lab is on the role of fibulin-5 in elastic fiber assembly and angiogenesis. Our studies of the fibulin-5 knockout mouse have shown that this mouse exhibits a phenotype of disorganized elastic fibers, lax skin, emphysematous lungs, arterial tortuosity and other vascular abnormalities. Recently, we have also observed that these mice show an increase in subcutaneous microvessels relative to wildtype mice. Using a polyvinyl alcohol sponge model, we have confirmed our in vivo observation by showing a significant increase in vascular invasion into sponges implanted subcutanously in the fibulin-5 null mice. Our working hypothesis, therefore, is that fibulin-5 acts as an inhibitor of angiogenesis and thus a lack of fibulin-5 results in deregulation of vessel growth and abnormal vascularization. Current research involves in vitro elastic fiber assembly assays to understand the relationship of fibulin-5 to elastic fiber formation, and in vivo and in vitro angiogenesis assays. Overall, our studies on fibulin-5 will provide a better understanding of the role that this protein plays in the development of elastogenic tissues and additionally, will allow us to determine the function of fibulin-5 in the development, maintenance and repair of blood vessels. Since anti-angiogenic factors play critical roles in many physiological and pathological conditions, the identification and charaterization of fibulin-5 as an angiogenesis inhibitor could provide a basis for developing new treatments aimed at inhibiting vessel growth.
The ELN-/- mouse was generated by Dr. Dean Y. Li at the University of Utah and the FBLN5-/- mouse was generated by Dr. Hiromi Yanagisawa at the University of Texas Southwestern Medical Center in Dallas. We currently maintain colonies of both of these knockout lines for our research.
Ling Li, M.D., Ph.D. – Research Associate
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Anatomy for Surgeons - fourth year medicine
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