Huiyan Zeng, PhD
Instructor of Medicine
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN 270F
Boston, MA 02215
Huiyan Zeng earned her Ph.D. in Division of Molecular Medicine, Department of Pharmacology, Boston University Medical Center, MA in 1998. She performed Postdoctoral training / NIH/NCI Postdoctoral fellowship (NRSA) at Beth Israel Deaconess Medical Center / Harvard Medical School with Dr. Debabrata Mukhopadhyay. In 2002, Dr. Zeng was appointed as an Instructor in Department of Pathology, Beth Israel Deaconess Medical Center / Harvard Medical School and obtained her NIH/NCI career development award.
Signaling Pathways of Angiogenesis
The research in my laboratory focuses on the molecular mechanism and signaling pathways that regulate 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-A165, we found that TR3 (mouse homologue, Nur77) was highly upregulated not only in VEGF-A165-stimulated endothelial cells, but also in microvessels in several examples of pathological angiogenesis in vivo, including adenovirus VEGF-A164-induced angiogenesis, skin wound healing and tumors. B16 melanoma growth and VEGF-A165-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-A165-induced angiogenesis.
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-A165-induced endothelial cell proliferation in vitro and angiogenesis in vivo. We found that another DSCR1 isoform, DSCR1-1L, was also upregulated by VEGF-A165 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-A165.
New and Noteworthy Publications
View all publications via PubMed >>
Qin L, Zhao D, Liu X, Nagy JA, Hoang MV, Brown LF, Dvorak HF,
Zeng H. Down syndrome candidate region 1 isoform 1 mediates angiogenesis through the calcineurin-NFAT pathway. Mol Cancer Res. 2006 Nov;4(11):811-20.
These studies identified a novel gene, DSCR1-1L, was upregulated specifically in tumor vessels, not in normal vessels and its role in VEGF-induced angiogenesis.
Zeng H*, Zhao D. Requirement of protein kinase D tyrosine phosphorylation for VEGF-A165-induced angiogenesis through its interaction and regulation of phospholipase Cgamma phosphorylation. J Biol Chem. 2006 Oct 27;281(43):32550-8. (*equal senior author).
These studies described the novel function of PKD in VEGF-induced angiogenesis.
Zeng H, Qin L, Zhao D, Tan X, Manseau EJ, Van Hoang M, Senger DR, Brown LF, Nagy JA, Dvorak HF. Orphan nuclear receptor TR3/Nur77 regulates VEGF-A-induced angiogenesis through its transcriptional activity. J Exp Med. 2006 Mar 20;203(3):719-29 (Corresponding author).
These studies described the novel function of Nur77 in angiogenesis.
Zeng H, Dvorak HF, Mukhopadhyay D. Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) peceptor-1 down-modulates VPF/VEGF receptor-2-mediated endothelial cell proliferation, but not migration, through phosphatidylinositol 3-kinase-dependent pathways. J Biol Chem. 2001 Jul 20;276(29):26969-79.
In these studies, we developed novel chimeric fusion receptors of VEGF receptor 1 and 2 to study the signaling pathways that were mediated by these two receptors.
Zeng H, Zhao D, Yang S, Datta K, Mukhopadhyay D. Heterotrimeric G alpha q/G alpha 11 proteins function upstream of vascular endothelial growth factor (VEGF) receptor-2 (KDR) phosphorylation in vascular permeability factor/VEGF signaling. J Biol Chem. 2003 Jun 6;278(23):20738-45.
This study was the first report that G protein played a role in growth factor receptor signaling.