The Secretion of Endothelin-1 by Microvascular Endothelial Cells from Human Benign Prostatic Hyperplasia is Inhibited by Vascular Endothelial Growth Factor

Abstract

Prostate growth seems to be influenced by paracrine factors like endothelin-1 (ET-1), originating from the microvascular endothelium. Recently, we reported on the first isolation and primary culture of microvascular endothelial cells (HPEC) derived from tissue of human benign prostatic hyperplasia (BPH). Therefore, direct investigation of growth factor secretion by HPEC is now possible. BPH tissue was cut into small cubes and gently squeezed after incubation with dispase. HPEC were cultured from the resulting cell suspension after a stepwise selection by use of superparamagnetic beads coated with antibodies against endothelial specific antigens. HPEC were characterized by flow cytometry. After the incubation of HPEC either with vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-alpha), or adenosine triphosphate (ATP), the secretion of ET-1 was measured by ELISA. HPEC showed a typical endothelial morphology. They were positive for von Willebrand factor and CD31. The ET-1 secretion of HPEC was inhibited by VEGF, but was unaffected by TNF-alpha or ATP. Furthermore, histochemistry revealed that in vivo microvascular endothelial cells were negative for ET-1. Because of the suppression by the widespread VEGF, it is unlikely that ET-1 from the microvascular endothelium acts as a growth factor in human BPH.

Regulation of soluble VEGFR-2 secreted by microvascular endothelial cells derived from human BPH

“…Therefore, it is thinkable that in the subsequent time periods the modification of the sVEGFR-2 secretion is more pronounced than observed in these experiments and reported before. [7][8][9] Furthermore, sVEGFR-2 decreased the proliferation of HPECs for 45% within 72 h. This significant effect results in a 50% lower cell population within 40 days (94.67% 13 ¼ 49.06%), which is a quite strong effect in relation to the slow growing BPH.…”

“…13,25 Previously, we demonstrated the effect of VEGF on the secretion of IL-6 and endothelin-1 by HPECs, suggesting a direct regulation of the paracrine activity of HPECs by VEGF. 7,8 As a major regulator for angiogenesis, VEGF activates a plethora of signaling pathways through two tyrosine kinase receptors VEGFR-1 and VEGFR-2. 26,27 But the major signaling receptor for VEGF, mediating most of its biological activities in endothelial cells, is VEGFR-2.…”

“…Recently, the isolation and culture of microvascular endothelial cells derived from tissue of human BPH (HPECs) was reported. [7][8][9] Furthermore, for the first time we reported that HPECs secrete the soluble vascular endothelial growth factor receptor-2 (sVEGFR-2). 9 Prostatic endothelial cells secrete paracrine factors that contribute to the growth of prostate epithelial and stromal cells.…”

“…[7][8][9] In this context, it has to be recognized that HPECs are benign cells that are not characterized by abnormal secretion and proliferation like malignant cells. In order to have standardized experimental settings, relatively short observation periods were used.…”

Toxicity of sorafenib: clinical and molecular aspects

“…VEGF also inhibits endothelin-1 secretion, a potent vasoconstrictor that plays an important role in vascular remodeling, particularly in resistance arteries [76]. In this context, VEGF pathway inhibition by sorafenib may cause an increase in endothelin-1 secretion, resulting in elevation of blood pressure.…”