Biomedical subjects

Renhai Cao

Publications and source records attributed to Renhai Cao.

22 records · Page 2Linked to original sources

PubMed2002

Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PlGF-1/VEGF heterodimers.

Tumor growth and metastasis require concomitant growth of new blood vessels, which are stimulated by angiogenic factors, including vascular endothelial growth factor (VEGF), secreted by most tumors. Whereas the angiogenic property and molecular mechanisms of VEGF have been well studied, the biological function of its related homolog, placenta growth factor (PlGF), is poorly understood. Here we demonstrate that PlGF-1, an alternatively spliced isoform of the PlGF gene, antagonizes VEGF-induced angiogenesis when both factors are coexpressed in murine fibrosarcoma cells. Overexpression of PlGF-1 in VEGF-producing tumor cells results in the formation of PlGF-1/VEGF heterodimers and depletion of the majority of mouse VEGF homodimers. The heterodimeric form of PlGF-1/VEGF lacks the ability to induce angiogenesis in vitro and in vivo. Similarly, PlGF-1/VEGF fails to activate the VEGFR-2-mediated signaling pathways. Further, PlGF-1 inhibits the growth of a murine fibrosarcoma by approximately 90% when PlGF-1-expressing tumor cells are implanted in syngeneic mice. In contrast, overexpression of human VEGF in murine tumor cells causes accelerated and exponential growth of primary fibrosarcomas and early hepatic metastases. Our data demonstrate that PlGF-1, a member of the VEGF family, acts as a natural antagonist of VEGF when both factors are synthesized in the same population of cells. The underlying mechanism is due to the formation of functionally inactive heterodimers.

Angiogenesis Inducing Agents↗

PubMed2002

Angiogenesis stimulated by PDGF-CC, a novel member in the PDGF family, involves activation of PDGFR-alphaalpha and -alphabeta receptors.

A newly discovered PDGF isoform, PDGF-CC, is expressed in actively angiogenic tissues such as placenta, some embryonic tissues, and tumors. We test the possibility that PDGF-CC promotes angiogenesis in vivo. The core domain (mature form) of human PDGF-CC is sufficiently potent to stimulate neovascularization in the mouse cornea. The corneal angiogenic response induced by PDGF-CC is robust although the area of neovascularization is smaller than those of FGF-2- and VEGF-stimulated angiogenesis. Similarly, PDGF-BB and PDGF-AB induce angiogenic responses virtually indistinguishable from PDGF-CC-stimulated vessels. In contrast, PDGF-AA displays only a weak angiogenic response in the mouse cornea. Although there was no significant difference in incorporation of mural cells to the newly formed blood vessels induced by PDGF-BB and -CC, the percentage of mural cell positive vessels induced by PDGF-AA was greater than those induced by FGF-2, PDGF-BB, and PDGF-CC. In the developing chick embryo, PDGF-CC induced branch sprouts from established blood vessels. In PDGF receptor-transfected endothelial cells, PDGF-CC activated the PDGF receptor alpha subunit (PDGFR-alpha). PDGF-CC, but not PDGF-AA, was able to activate PDGFR-beta receptor in endothelial cells that coexpress both alpha and beta forms of receptors. Thus, the PDGF-CC-mediated angiogenic response is most likely transduced by PDGF-alphaalpha and -alphabeta receptors. These data demonstrate that the PDGF family is a complex and important group of proangiogenic factors.

Allantois↗

PubMed2002

Deletion of the laminin alpha4 chain leads to impaired microvessel maturation.

The laminin alpha4 chain, a component of laminin-8 and -9, is expressed in basement membranes, such as those beneath endothelia, the perineurium of peripheral nerves, and around developing muscle fibers. Laminin alpha4-null mice presented with hemorrhages during the embryonic and neonatal period and had extensive bleeding and deterioration of microvessel growth in experimental angiogenesis, as well as mild locomotion defects. Histological examination of newborn mice revealed delayed deposition of type IV collagen and nidogen into capillary basement membranes, and electron microscopy showed discontinuities in the lamina densa. The results demonstrate a central role for the laminin alpha4 chain in microvessel growth and, in the absence of other laminin alpha chains, in the composition of endothelial basement membranes.

Anemia↗

PubMed2002

Kringle structures and antiangiogenesis.

The quiescent vascular system in the adult body represents the balanced net outcome of overproduction of endogenous angiogenesis inhibitors and reduced levels of angiogenic factors. While these inhibitors are expressed under physiological conditions, they are also generated in association with tumor growth. Angiostatin is such a specific angiogenesis inhibitor produced by tumors. It inhibits primary and metastatic tumor growth by blocking tumor angiogenesis. Encouraged by its potent anti-tumor activity, angiostatin is in clinical trials for cancer therapy. Angiostatin contains the first four triple loop structures, known as kringle domains, of plasminogen. The disulfide bond-linked kringle architectures are essential for the antiangiogenic activity of angiostatin. Based on this initial finding, recent work shows that kringle fragments of several other proteins also inhibit angiogenesis. Thus, kringle domains may provide a structural basis for identification of novel angiogenesis inhibitors. Surprisingly, most kringles only inhibit angiogenesis when cleaved as fragments from their parental proteins that lack antiangiogenic activity. These findings suggest that they are cryptic fragments hidden in large protein molecules. Thus, proteolytic processing plays a critical role in down regulation of angiogenesis. The kringle structure may provide the first example of a conserved architecture that specifically inhibits blood vessel growth. This review will focus on the structural and functional relationships of kringle domains in regulation of angiogenesis and tumor growth.

Angiogenesis Inhibitors↗