A Novel Human-Specific Soluble Vascular Endothelial Growth Factor Receptor 1

Abstract

Abstract-A human-specific splicing variant of vascular endothelial growth factor (VEGF) receptor 1 (Flt1) was discovered, producing a soluble receptor (designated sFlt1-14) that is qualitatively different from the previously described soluble receptor (sFlt1) and functioning as a potent VEGF inhibitor. sFlt1-14 is generated in a cell type-specific fashion, primarily in nonendothelial cells. Notably, in vascular smooth muscle cells, all Flt1 messenger RNA is converted to sFlt1-14, whereas endothelial cells of the same human vessel express sFlt1. sFlt1-14 expression by vascular smooth muscle cells is dynamically regulated as evidenced by its upregulation on coculture with endothelial cells or by direct exposure to VEGF. Increased production of soluble VEGF receptors during pregnancy is entirely attributable to induced expression of placental sFlt1-14 starting by the end of the first trimester. Expression is dramatically elevated in the placenta of women with preeclampsia, specifically induced in abnormal clusters of degenerative syncytiotrophoblasts known as syncytial knots, where it may undergo further messenger RNA editing. sFlt1-14 is the predominant VEGF-inhibiting protein produced by the preeclamptic placenta, accumulates in the circulation, and hence is capable of neutralizing VEGF in distant organs affected in preeclampsia. Together, these findings revealed a new natural VEGF inhibitor that has evolved in humans, possibly to protect nonendothelial cells from adverse VEGF signaling. Furthermore, the study uncovered the identity of a VEGF-blocking protein implicated in preeclampsia. Key Words: VEGF Ⅲ soluble VEGF receptor Ⅲ splicing Ⅲ preeclampsia Ⅲ vascular smooth muscle cell V ascular endothelial growth factor (VEGF) is the key factor promoting vasculogenesis and angiogenesis in the embryo and the factor orchestrating most, if not all, processes of adult neovascularization. In addition, VEGF performs nonvascular developmental functions and plays a number of homeostatic roles in the adult. The latter includes maintenance of endothelial fenestrations, a role in vasodilatation, and neurogenic and neurotrophic activities, among others. 1,2 Not surprisingly, therefore, VEGF is under a tight spatial and temporal regulation, and even a moderate deviation from its exquisite dosage control or perturbation of its precise morphogenetic gradients is detrimental for proper development and organ homeostasis. 3,4 Among the multiple layers of VEGF control, natural VEGF inhibitors, primarily soluble VEGF receptors, are likely to be important. Indeed, VEGF receptor-1 (Flt1) messenger RNA (mRNA) may undergo alternative splicing in a way that the encoded protein retains the ligand-binding domain but is devoid of the membrane-spanning and intracellular kinase domains, hence functioning as a VEGF-trapping soluble receptor. This secreted protein (designated sFlt1) is a potent inhibitor of both VEGF-A, VEGF-B, and placental growth factor. 2 It is widely used as a research tool for VEGF inhibition and, more recently, also harnessed...

Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction

“…sFlt-1 e15a (or sFlt-1 v14) is the main sFlt-1 variant in placenta 15 that has only been described recently. 15,16 Endothelium is another major tissue source of sFlt-1. When administered to HUVECs, PPIs dose dependently reduced sFlt-1 secretion ( Figure 1D) but not mRNA expression ( Figure S1D and S1E) of the 2 sFlt-1 variants, sFlt-1 e15a and sFlt-1 i13.…”

Placental-Specific sFLT-1 e15a Protein Is Increased in Preeclampsia, Antagonizes Vascular Endothelial Growth Factor Signaling, and Has Antiangiogenic Activity

“…7 Using the G4635 antibody, we performed immunofluorescence and verified that sFLT-1 e15a protein is indeed highly expressed in the syncytiotrophoblast layer of the placenta ( Figure 1F-1H). …”

“…6,7,11 To our knowledge, functional studies examining sFLT-1 e15a protein bioactivity have been limited to one experiment showing it competitively inhibits VEGF-induced activation (phosphorylation) of VEGFR2 in porcine endothelial cells. 7 Furthermore, serum levels have not been reported. A possible explanation is the lack of commercially available reagents, notably an sFLT-1 e15a ELISA.…”

Mechanisms of Hypertension and Renal Injury During Vascular Endothelial Growth Factor Signaling Inhibition

“…8 Different soluble splice variants of the VEGFR-1, consisting of the extracellular part of the VEGFR-1, have been described. 9,10 These variants can exert a negative regulatory role by sequestrating VEGF-A. In preeclampsia, the circulating concentration of sFlt-1-e15a, also known as sFlt-1-14, and originating from placental syncythiotrophoblasts, is massively increased, playing a dominant role in the pathophysiology of this condition.…”

“…In preeclampsia, the circulating concentration of sFlt-1-e15a, also known as sFlt-1-14, and originating from placental syncythiotrophoblasts, is massively increased, playing a dominant role in the pathophysiology of this condition. [9][10][11] VEGF is also known to control different processes during neurodevelopment. Of interest with regard to BP homeostasis, transgenic mice with low VEGF levels have defects in the regulation of resistance arteries because of dysfunction of the synapses between autonomic nerve endings and vascular smooth muscle cells and to an impaired vascular smooth muscle cell contractile response.…”