semaxinib and Pre-Eclampsia

Endothelial dysfunction is a primary feature of preeclampsia, a pregnancy complication associated with an increased future cardiovascular risk for mother and offspring. Endothelial colony forming cells (ECFC) are endothelial progenitor cells that participate in vasculogenesis and endothelial repair.. We hypothesized that the number and functional properties of fetal cord blood-derived ECFCs are reduced in preeclampsia compared to uncomplicated pregnancy (controls), and asked if adverse effects of preeclampsia on ECFC function are reversed by 1,25 (OH)2 vitamin D3.. This was a nested, case-control study. Forty women with uncomplicated pregnancy and 33 women with PE were recruited at Magee-Womens Hospital (USA) or at Hannover Medical School (Germany).. Time to ECFC colony appearance in culture, and number of colonies formed, were determined. Functional abilities of ECFCs were assessed in vitro by tubule formation in Matrigel assay, migration, and proliferation. ECFC function was tested in the presence or absence of 1,25 (OH)2 vitamin D3, and after vitamin D receptor (VDR) or VEGF signaling blockade.. The number of cord ECFC colonies was lower (P = 0.04) in preeclampsia compared to controls. ECFCs from preeclampsia showed reduced proliferation (P<0.0001), formed fewer tubules (P = 0.02), and migrated less (P = 0.049) than control. Vitamin D3 significantly improved preeclampsia ECFC functional properties. VDR- or VEGF blockade reduced tubule formation, partially restorable by vitamin D3.. Fetal ECFCs from preeclamptic pregnancies are reduced in number and dysfunctional. Vitamin D3 had rescuing effects. This may have implications for the increased cardiovascular risk associated with preeclampsia.

Topics: Adult; Calcitriol; Case-Control Studies; Cell Movement; Cell Proliferation; Cells, Cultured; Endothelial Cells; Female; Fetal Blood; Humans; Indoles; Microtubules; Pre-Eclampsia; Pregnancy; Pyrroles; Receptors, Calcitriol; RNA Interference; RNA, Small Interfering; Signal Transduction; Vascular Endothelial Growth Factor A

The main pathogenic feature of preeclampsia is maternal endothelial dysfunction that results from impaired angiogenesis and reduced endothelial repair capacity. In addition, preeclampsia risk is associated with vitamin D deficiency. We hypothesized that vitamin D(3) stimulates proangiogenic properties of endothelial colony-forming cells (ECFCs). ECFCs were obtained and cultured from cord blood and characterized by immunocytochemistry and flow cytometry. Proliferation, total length of tubule formation on Matrigel, expression of VEGF mRNA, and pro-matrix metalloproteinases (MMP)-2 activity were assessed after treatment of ECFCs with vitamin D(3). Specificity of the observed effects was tested by blocking the vitamin D receptor (VDR) or the VEGF signaling pathway. ECFCs treated with 10 nM vitamin D(3) showed a 1.27 times higher tubule formation compared with vehicle-treated controls (1.27 ± 0.19) as well as a 1.36 times higher proliferation rate (1.36 ± 0.06). Vitamin D(3) induced pro-MMP-2 activity (1.29 ± 0.17) and VEGF mRNA levels (1.74 ± 0.73) in ECFCs. VDR blocking by pyridoxal-5-phosphate (0.73 ± 0.19) or small interfering RNA (0.75 ± 0.17) and VEGF inhibition by Su5416 (0.56 ± 0.16) or soluble fms-like tyrosine kinase-1 (0.7 ± 0.14) reduced tubule formation and pro-MMP-2 activity (pyridoxal-5-phosphate: 0.84 ± 0.09; Su5416: 0.79 ± 0.11; or sFlt: 0.88 ± 0.13). This effect was neutralized by vitamin D(3). Consequently, vitamin D(3) significantly promoted angiogenesis in ECFCs in vitro possibly due to an increase in VEGF expression and pro-MMP-2 activity. Since angiogenesis is a crucial feature in the pathophysiology of preeclampsia these findings could explain the positive influence of vitamin D(3) in reducing preeclampsia risk.

Topics: Angiogenesis Inhibitors; Cell Proliferation; Cells, Cultured; Cholecalciferol; Endothelial Cells; Female; Fetal Blood; Flow Cytometry; Humans; Immunohistochemistry; Indoles; Matrix Metalloproteinase 2; Neovascularization, Physiologic; Pre-Eclampsia; Pregnancy; Pyridoxal Phosphate; Pyrroles; Receptors, Calcitriol; Risk; Signal Transduction; Stem Cells; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Maternal and placental angiogenic abnormalities are a common feature of preeclampsia. The aim of this study was to determine if endothelial cells from women with preeclampsia exhibit different angiogenic responses compared to healthy cells. Using the endothelial tube formation assay, we have shown that primary human umbilical vein endothelial cells (HUVECs) isolated from women with preeclampsia display greater levels of in vitro angiogenic branching compared to cells from healthy women. A comparable increase in tube formation was observed in healthy cells cultured at 0.5% O(2). Vascular endothelial growth factor (VEGF) receptor inhibition resulted in a decrease in angiogenesis in both healthy hypoxic cells and cells from women with preeclampsia. These findings demonstrate that HUVECs from women with preeclampsia exhibit inherent differences in their angiogenic capacity which are apparent in the absence of placental or maternal factors.

Topics: Adult; Analysis of Variance; Angiogenesis Inhibitors; Case-Control Studies; Cell Hypoxia; Cells, Cultured; Endothelial Cells; Female; Humans; Indoles; Neovascularization, Pathologic; Neovascularization, Physiologic; Pre-Eclampsia; Pregnancy; Protein Kinase Inhibitors; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Umbilical Veins; Young Adult