Angiogenesis, the growth of new blood vessels, is critical for embryonic development and pathogenesis as well as treatment of cardiovascular disease and cancer. Arteriogenesis is a key angiogenic process that involves the radial growth of arteries and is more efficient in increasing blood flow than the better-known sprouting angiogenesis, or the growth of new capillaries. To better understand arteriogenesis, we study the biochemical, cellular, and hemodynamic mechanisms underlying this process, with a focus on the Notch and Ephrin-B2 signaling pathways, which are uniquely expressed in arteries but not veins, and control arterial differentiation. We utilize advanced mouse genetics to spatially and temporally control gene expression in the endothelium lining the vessel walls. To understand arteriogenic processes in living animals, we measure vascular topology and hemodynamics using imaging modalities that include our custom-built two-photon microscope. Our animal studies are complemented with in vitro cellular and molecular approaches that explore arteriogenesis in both normal and disease settings. Consequently, our research consists of several interrelated yet distinct projects:
Embryonic Arterial Venous Differentiation. We aim to identify molecular regulators of arterial cell fate determination and morphogenesis during vascular development. We primarily focus on the origin and morphogenesis of the dorsal aorta, the first major artery to form in the body.
Arteriovenous malformation (AVM). AVMs are abnormal shunts between arteries and veins. Arterialization of capillaries, via arteriogenesis, may lead to AVM formation. Specifically, we study the pathogenesis and regression of brain AVMs using two-photon imaging through a cranial “window” in living animals.
Ischemia. The body responds to arterial occlusions by inducing local arteriogenesis to restore perfusion to ischemic tissue. Clinical evidence suggests that patients who undergo less efficient arteriogenesis, developing fewer or smaller collateral arteries, are more likely progress to ischemia. The factors governing the variability in arteriogenesis in patients are unknown. Our goal is to identify pro-arteriogenic factors as potential therapeutic targets to enhance the body’s natural defense to arterial occlusions.
Cancer. Solid tumors induce arteriogenesis to support their growth. We investigate the molecular stimulators of arteriogenesis in tumor progression and regression, particularly in hepatocellular carcinoma, which is characterized by large and highly arterialized tumor masses.
Our research into the cell signaling events that govern arterial growth may ultimately lead to rational design of therapeutics for the treatment of major human diseases.
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