Estradiol Stimulates Capillary Formation by Human Endothelial Progenitor Cells: Role of ER-α/β, Heme Oxygenase-1 and Tyrosine Kinase

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2010-07, Vol.56 (3), p.397-404
• Main Authors: Baruscotti, Isabella, Barchiesi, Federica, Jackson, Edwin K, Imthurn, Bruno, Stiller, Ruth, Kim, Jai-Hyun, Schaufelberger, Sara, Rosselli, Marinella, Hughes, Christopher CW, Dubey, Raghvendra K.
• Format: Article
• Language: English
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.110.153262

Endothelial progenitor cells (EPCs) repair damaged endothelium and promote capillary formation, processes involving receptor tyrosine kinases (RTKs) and heme oxygenase-1 (HO-1). Because estradiol augments vascular repair, we hypothesize that estradiol increases EPC proliferation and capillary formation via RTK activation and induction of HO-1. Physiological concentrations of estradiol (10nmol/L) increased EPC-induced capillarysprout and lumenformation in matrigel/fibrin/collagensystems. Propyl-pyrazole-triol [PPT; 100nmol/L; estrogen receptor (ER)-α agonist], but not by diarylpropionitrile (ER-β agonist), mimicked the stimulatory effects of estradiol on capillary formation, and methyl-piperidino-pyrazole (ER-α antagonist) abolished the effects of estradiol and PPT. Three different RTK activators [vascular endothelial growth factor (VEGF), hepatocyte growth factor and stromal derived growth factor-1] mimicked the capillary-stimulating effects of estradiol and PPT. SU5416 (RTK inhibitor)blocked the stimulatory effects of estradiol and PPT on capillary formation. Estradiol increased HO-1 expressionby 2–3 fold, an effect blocked by SU5416, and PPT mimicked the effects of estradiol on HO-1. The ability of estradiol to enhance capillary formation, increaseexpressionof HO-1, and augment phosphorylation ofERK1/2, Akt, and VEGF receptor-2 were mimicked by its cell-impermeable analog BSA-estradiol. Actinomycin (transcription inhibitor) did not alter the effects of estradiol on RTK activity or VEGF secretion. We conclude that estradiol via ER-α promotes EPC-mediated capillary formation by a mechanism that involves non-genomic activation of RTKs and HO-1 activation. Estradiol in particular and ER-αagonists in general may promote healing of injured vascular beds by promoting EPC activity leading to more rapid endothelial recovery and capillary formation following injury.