Huiyan Zheng Lab
The research in our laboratory has focused on the molecular mechanism of pathological angiogenesis. Pathological angiogenesis is a hallmark of many diseases including ischemic heart disease, wound healing, cancer and inflammation. Vascular endothelial growth factor (VEGF) is one of the most important angiogenesis factors because of its potency and relatively selectivity for vascular endothelium.
In gene profile studies of cultured endothelial cells exposed to VEGF-A
165, we found that TR3 (mouse homologue, Nur77) was highly upregulated not only in VEGF-A
165-stimulated endothelial cells, but also in microvessels in several examples of pathological angiogenesis
in vivo, including adenovirus VEGF-A
164-induced angiogenesis, skin wound healing and tumors. B16 melanoma growth and VEGF-A
165-stimulated-microvessel permeability were completely inhibited in Nur77 knock out (nur77-/-) mice. Overexpression of TR3/Nur77 was sufficient by itself to induce angiogenesis and also that TR3/Nur77 had an essential role in VEGF-A
Down syndrome candidate region 1 (DSCR1) is another gene that is identified to be upregulated by VEGF. DSCR1 can be expressed as four isoforms, one of which, isoform 4 (DSCR1-4), has recently been found to provide a negative feedback loop that inhibits VEGF-A
165-induced endothelial cell proliferation in vitro and angiogenesis in vivo. We found that another DSCR1 isoform, DSCR1-1L, was also upregulated by VEGF-A
165 in cultured endothelial cells and is strongly expressed in several types of pathological angiogenesis in vivo. Moreover, DSCR1-1L and DSCR1-4 were expressed in tumor microvascular structure, not in tumor cells, nor in normal vessel, either. DSCR1-1L, unlike DSCR1-4, potently activates angiogenesis and could be an attractive target for anti-angiogenesis therapy.
Another project is to study the role of protein kinase D in VEGF-induced angiogenesis. We demonstrate that PKD interacts with PLCg and becomes tyrosine phosphorylated upon VEGF stimulation, leading to PLCg activation and angiogenic response of VEGF-A
Selected Recent Publications
Zeng H, Qin LL, Zhao D, Tan X, Manseau EJ, Hoang MV, Senger DR, Brown LF, Nagy JA, Dvorak HD. Orphan Nuclear Receptor TR3/Nur77 regulates the early steps of VEGF-A-induced angiogenesis through its transcriptional activity.
J Exp Med. 2006, 203: 719-729 (
Qin L, Zeng H, Zhao D. Requirement of PKD tyrosine phosphorylation for VEGF-A165-induced angiogenesis through its interaction and regulation of phospholipase Cgamma phosphorylation.
J Biol Chem. 2006, 281(43): 32550-8
Qin LL, Zhao D, Liu L, Nagy JA, Hoang MV, Brown LF, Dvorak HF, Zeng H. Down Syndrome Candidate Region 1 Isoform 1 (DSCR1-1L)-mediates angiogenesis through the Calcineurin-NFAT pathway. Mol Cancer Res. 2006, 4(11) (in press).