Angiogenesis in gestational vascular complications

Abstract 

Vascular endothelial growth factor (VEGF) is a key player in vasculogenesis and angiogenesis in the embryo, and essential in neovascularization in adults. Natural VEGF inhibitors such as soluble VEGF receptors, among them the soluble VEGF-trapping receptor Flt1 (sFlt1), participate in VEGF regulation. Decreased levels of VEGF and increased levels of sFlt1 have been implicated in the pathophysiology of preeclampsia. We discovered a soluble receptor, sFlt1-14, qualitatively different from sFlt1 and a potent VEGF inhibitor. It is generated in a cell type specific fashion, primarily in nonendothelial cells, most notably in vascular smooth muscle cells. We showed that increased production of soluble VEGF receptors in pregnancy is owing to expression of sFlt1-14, from the end of the first trimester to term. This expression is markedly elevated in preeclampsia, and is expressed chiefly by syncitial knots.

In subsequent studies we found that sFlt1 is a strong heparin binder: this capability enables it to stay attached to blood vessels and to the placenta. Ex vivo, sFlt1 can be heparin displaced to medium from aortic segments and placental villi. In vivo, pregnant women treated with the low molecular weight heparin (LMWH) have elevated sFlt1 levels in their circulations. Interestingly, LMWH raised VEGF levels over and above the increase in sFlt1 levels in these patients. Heparanaseoverexpressing non-pregnant as well as pregnant transgenic mice present elevated levels of sFlt1 in their circulations. Ex vivo prevention of heparanase maturation through cathepsin L inhibition, or targeting heparanase directly with a neutralizing antibody, both resulted in a marked reduction in sFlt1 secretion to medium of normal and preeclamptic placental expiants.

These findings uncover a new level of regulation that controls sFlt1 bio-distribution, and directs it to function in the vicinity of its producing cell. Heparanase or LMWH has the ability to liberate sFlt1 from its retention, so this process may be a potential target for preeclampsia treatment.

Keywords:  sFlt1-14 , VEGF , Heparanase , Preeclampsia

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