TY - JOUR
T1 - VEGFR2 is activated by high-density lipoproteins and plays a key role in the proangiogenic action of HDL in ischemia
AU - Cannizzo, Carla M.
AU - Adonopulos, Aaron A.
AU - Solly, Emma L.
AU - Ridiandries, Anisyah
AU - Vanags, Laura Z.
AU - Mulangala, Jocelyne
AU - Yuen, Sui Ching G.
AU - Tsatralis, Tania
AU - Henriquez, Rodney
AU - Robertson, Stacy
AU - Nicholls, Stephen J.
AU - Di Bartolo, Belinda A.
AU - Ng, Martin K.C.
AU - Ting Lam, Yuen
AU - Bursill, Christina A.
AU - Tan, Joanne T.M.
PY - 2018/6/1
Y1 - 2018/6/1
N2 -
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 formediating 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 rHDLinduced phosphorylation of VEGFR2, ERK1/2, p38MAPK, and tubule formation. In a murine model of ischemiadriven 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.
AB -
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 formediating 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 rHDLinduced phosphorylation of VEGFR2, ERK1/2, p38MAPK, and tubule formation. In a murine model of ischemiadriven 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.
KW - Angiogenesis
KW - Apoa-I
KW - Hypoxia
UR - http://www.scopus.com/inward/record.url?scp=85048208085&partnerID=8YFLogxK
U2 - 10.1096/fj.201700617R
DO - 10.1096/fj.201700617R
M3 - Article
C2 - 29401597
AN - SCOPUS:85048208085
SN - 0892-6638
VL - 32
SP - 2911
EP - 2922
JO - The FASEB Journal
JF - The FASEB Journal
IS - 6
ER -