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VEGFR2 is activated by high‐density lipoproteins and plays a key role in the proangiogenic action of HDL in ischemia
Author(s) -
Cannizzo Carla M.,
Adonopulos Aaron A.,
Solly Emma L.,
Ridiandries Anisyah,
Vanags Laura Z.,
Mulangala Jocelyne,
Yuen Sui Ching G.,
Tsatralis Tania,
Henriquez Rodney,
Robertson Stacy,
Nicholls Stephen J.,
Di Bartolo Belinda A.,
Ng Martin K. C.,
Lam Yuen Ting,
Bursill Christina A.,
Tan Joanne T. M.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700617r
Subject(s) - angiogenesis , phosphorylation , ischemia , p38 mitogen activated protein kinases , hypoxia (environmental) , kinase insert domain receptor , neovascularization , mapk/erk pathway , vascular endothelial growth factor , microbiology and biotechnology , chemistry , vascular endothelial growth factor a , medicine , endocrinology , cancer research , pharmacology , biology , vegf receptors , organic chemistry , oxygen
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. FASEB J. 32, 2911–2922 (2018). www.fasebj.org