TY - JOUR
T1 - Local retention versus systemic release of soluble VEGF receptor-1 are mediated by heparin-binding and regulated by heparanase
AU - Sela, Shay
AU - Natanson-Yaron, Shira
AU - Zcharia, Eyal
AU - Vlodavsky, Israel
AU - Yagel, Simcha
AU - Keshet, Eli
PY - 2011/4/29
Y1 - 2011/4/29
N2 - Rationale: The vascular endothelial growth factor (VEGF) decoy receptor soluble VEGF-R1 (sVEGF-R1) is thought to protect the cells that produce it from adverse VEGF signaling. To accomplish this role, a mechanism for pericellular retention of sVEGF-R1 is required. Local retention may also prevent the accumulation of high circulating levels of sVEGF-R1 and resulting interference with homeostatic VEGF functions in remote organs. Objective: To reveal natural storage depots of sVEGF-R1 and determine mechanisms underlying its pericellular retention. To uncover natural mechanisms regulating its systemic release. Methods and Results: We show that both the canonical and human-specific isoforms of sVEGF-R1 are strongly bound to heparin. sVEGF-R1 produced by vascular smooth muscle cells is stored in the vessel wall and can be displaced from isolated mouse aorta by heparin. Another major reservoir of sVEGF-R1 is the placenta. Heparin increases the level of sVEGF-R1 released by cultured human placental villi, and pregnant women treated with low molecular weight heparin showed markedly elevated levels of sVEGF-R1 in the circulation. Heparanase is expressed in human placenta at the same locales as sVEGF-R1, and its transgenic overexpression in mice resulted in a marked increase in the levels of circulating sVEGF-R1. Conversely, heparanase inhibition, by either a neutralizing antibody or by inhibition of its maturation, reduced the amounts of sVEGF-R1 released from human placental villi, indicating a natural role of heparanase in sVEGF-R1 release. Conclusions: Together, the findings uncover a new level of regulation governing sVEGF-R1 retention versus release and suggest that manipulations of the heparin/heparanase system could be harnessed for reducing unwarranted release of sVEGF-R1 in pathologies such as preeclampsia.
AB - Rationale: The vascular endothelial growth factor (VEGF) decoy receptor soluble VEGF-R1 (sVEGF-R1) is thought to protect the cells that produce it from adverse VEGF signaling. To accomplish this role, a mechanism for pericellular retention of sVEGF-R1 is required. Local retention may also prevent the accumulation of high circulating levels of sVEGF-R1 and resulting interference with homeostatic VEGF functions in remote organs. Objective: To reveal natural storage depots of sVEGF-R1 and determine mechanisms underlying its pericellular retention. To uncover natural mechanisms regulating its systemic release. Methods and Results: We show that both the canonical and human-specific isoforms of sVEGF-R1 are strongly bound to heparin. sVEGF-R1 produced by vascular smooth muscle cells is stored in the vessel wall and can be displaced from isolated mouse aorta by heparin. Another major reservoir of sVEGF-R1 is the placenta. Heparin increases the level of sVEGF-R1 released by cultured human placental villi, and pregnant women treated with low molecular weight heparin showed markedly elevated levels of sVEGF-R1 in the circulation. Heparanase is expressed in human placenta at the same locales as sVEGF-R1, and its transgenic overexpression in mice resulted in a marked increase in the levels of circulating sVEGF-R1. Conversely, heparanase inhibition, by either a neutralizing antibody or by inhibition of its maturation, reduced the amounts of sVEGF-R1 released from human placental villi, indicating a natural role of heparanase in sVEGF-R1 release. Conclusions: Together, the findings uncover a new level of regulation governing sVEGF-R1 retention versus release and suggest that manipulations of the heparin/heparanase system could be harnessed for reducing unwarranted release of sVEGF-R1 in pathologies such as preeclampsia.
KW - heparan sulfate
KW - heparanase
KW - preeclampsia
KW - soluble VEGF-R1
KW - vascular smooth muscle cell
UR - http://www.scopus.com/inward/record.url?scp=79955582750&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.110.239665
DO - 10.1161/CIRCRESAHA.110.239665
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C2 - 21415391
AN - SCOPUS:79955582750
SN - 0009-7330
VL - 108
SP - 1063
EP - 1070
JO - Circulation Research
JF - Circulation Research
IS - 9
ER -