VEGFR2 is activated by high-density lipoproteins and plays a key role in the proangiogenic action of HDL in ischemia.

Abstract

High-density lipoproteins augment hypoxia-induced angiogenesis by inducing the key angiogenic vascular endothelial growth factor A (VEGFA) and total protein levels of its receptor 2 (VEGFR2). The activation/phosphorylation of VEGFR2 is critical for mediating downstream, angiogenic signaling events. This study aimed to determine whether reconstituted high-density lipoprotein (rHDL) activates VEGFR2 phosphorylation and the downstream signaling events and the importance of VEGFR2 in the proangiogenic effects of rHDL in hypoxia. In vitro, rHDL increased VEGFR2 activation and enhanced phosphorylation of downstream, angiogenic signaling proteins ERK1/2 and p38 MAPK in hypoxia. Incubation with a VEGFR2-neutralizing antibody attenuated rHDL-induced phosphorylation of VEGFR2, ERK1/2, p38 MAPK, and tubule formation. In a murine model of ischemia-driven neovascularization, rHDL infusions enhanced blood perfusion and augmented capillary and arteriolar density. Infusion of a VEGFR2-neutralizing antibody ablated those proangiogenic effects of rHDL. Circulating Sca1+/CXCR4+ angiogenic progenitor cell levels, important for neovascularization in response to ischemia, were higher in rHDL-infused mice 3 d after ischemic induction, but that did not occur in mice that also received the VEGFR2-neutralizing antibody. In summary, VEGFR2 has a key role in the proangiogenic effects of rHDL in hypoxia/ischemia. These findings have therapeutic implications for angiogenic diseases associated with an impaired response to tissue ischemia.-Cannizzo, C. M., Adonopulos, A. A., Solly, E. L., Ridiandries, A., Vanags, L. Z., Mulangala, J., Yuen, S. C. G., Tsatralis, T., Henriquez, R., Robertson, S., Nicholls, S. J., Di Bartolo, B. A., Ng, M. K. C., Lam, Y. T., Bursill, C. A., Tan, J. T. M. VEGFR2 is activated by high-density lipoproteins and plays a key role in the proangiogenic action of HDL in ischemia.

• Authors: Carla M Cannizzo, Aaron A Adonopulos, Emma L Solly, Anisyah Ridiandries, Laura Z Vanags, Jocelyne Mulangala, Sui Ching G Yuen, Tania Tsatralis, Rodney Henriquez, Stacy Robertson, Stephen J Nicholls, Belinda A Di Bartolo, Martin K C Ng, Yuen Ting Lam, Christina A Bursill, Joanne T M Tan
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 32 Issue 6 Pg. 2911-2922 (06 2018) ISSN: 1530-6860 [Electronic] United States
• PMID: 29401597 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inducing Agents
• Antibodies, Neutralizing
• Lipoproteins, HDL
• KDR protein, human
• Kdr protein, mouse
• Vascular Endothelial Growth Factor Receptor-2
• Extracellular Signal-Regulated MAP Kinases

Topics

• Angiogenesis Inducing Agents (metabolism)
• Animals
• Antibodies, Neutralizing (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Humans
• Ischemia (metabolism, pathology, physiopathology)
• Lipoproteins, HDL (antagonists & inhibitors, metabolism)
• MAP Kinase Signaling System
• Mice
• Neovascularization, Physiologic
• Phosphorylation (drug effects)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)