Brain angiogenesis, blood-brain barrier and stroke
The blood vessels of the brain are absolutely critical; for example, interruption of brain blood flow can result in devastating stroke. We study Gpr124, a G protein-coupled receptor expressed on brain vasculature.We showed that gene knockout of Gpr124 results in a near-total loss of angiogenic invasion into the embryonic brain, resulting in forebrains that are essentially avascular. The few blood vessels that successfully enter the brain in Gpr124 ko mice aggregate abnormally into glomeruloid aggregates that are hemorrhagic and result in embryonic lethality (Kuhnert et al., Science, 2010). Here, we use genetic and biochemical techniques to study how Gpr124 regulates brain blood vessels during disorders such as stroke and brain tumors, and mechanisms by which Gpr124 transmits signals. In a larger sense, we are generally interested in developing new therapies for stroke which modulate the highly specialized blood-brain barrier.
Endothelial regulation of host organ physiology
All tissues of the body have a rich capillary network. We are interested in how these blood vessels not merely carry blood supply to organs by actually govern organ physiology and metabolism. Using inhibitors of Vascular Endothelial Growth Factor (VEGF) we can regress the capillary networks of adult organs and study effects on physiology. For example, VEGF inhibition causes liver sinusoidal capillary regression and induces hepatic production of erythropoietin (Epo), with increased red blood cell production and hematocrit >70% (Tam, Wei et al., Nature Medicine, 2006). Further, VEGF inhibition with its capillary regression leads to activation of the liver hypoxia/HIF-2a pathway, which transactivates IRS2 and dramatically enhances liver insulin signaling (Wei et al., Nature Medicine, 2013a; Taniguchi et al., Nature Medicine, 2013b). This crosstalk between the liver hypoxia and insulin signaling pathways allows VEGF inhibitors to effectively treat mouse models of diabetes and suggests that either VEGF inhibitors or HIF stabilizers could be novel diabetes therapeutics. We are interested in additional hepatocyte-centric mechanisms by which VEGF inhibition or the HIF pathway regulates glucose tolerance, and how this pathway can be pharmacologically manipulated for diabetes treatment.
Roles of microRNAs in vascular biology.
Another area of interest is how the 22 nt microRNAs control blood vessel development and physiology. We showed previously that the microRNA miR-126 is an essential regulator of embryonic angiogenesis and vascular integrity, since miR-126 knockout mice exhibit partially penetrant embryonic lethality with edema, hemorrhage and angiogenic deficits (Kuhnert et al., Development 2008). Our current interests involve using conditional floxed miR-126 alleles to investigate functions of this miRNA during adult pathophysiologic processes.