Estradiol stimulates capillary formation by human endothelial progenitor cells: role of estrogen receptor-{alpha}/{beta}, heme oxygenase 1, and tyrosine kinase

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2010-09, 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 C W, Dubey, Raghvendra K
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Blotting, Western; Capillaries - drug effects; Capillaries - metabolism; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Enzyme-Linked Immunosorbent Assay; Estradiol - pharmacology; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - metabolism; Flow Cytometry; Heme Oxygenase-1 - metabolism; Humans; Mitogen-Activated Protein Kinase 3 - metabolism; Neovascularization, Physiologic - drug effects; Phosphorylation - drug effects; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Vascular Endothelial Growth Factor - metabolism; Signal Transduction - drug effects; Stem Cells
• ISSN: 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 (10 nmol/L) increased EPC-induced capillary sprout and lumen formation in matrigel/fibrin/collagen systems. Propyl-pyrazole-triol (PPT; 100 nmol/L; estrogen receptor [ER]-alpha agonist), but not diarylpropionitrile (ER-beta agonist), mimicked the stimulatory effects of estradiol on capillary formation, and methyl-piperidino-pyrazole (ER-alpha antagonist) abolished the effects of estradiol and PPT. Three different RTK activators (vascular endothelial growth factor, 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 expression by 2- to 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, increase expression of HO-1, and augment phosphorylation of extracellular signal-regulated kinase 1/2, Akt, and vascular endothelial growth factor receptor 2 was mimicked by its cell-impermeable analog BSA estradiol. Actinomycin (transcription inhibitor) did not alter the effects of estradiol on RTK activity or vascular endothelial growth factor secretion. We conclude that estradiol via ER-alpha promotes EPC-mediated capillary formation by a mechanism that involves nongenomic activation of RTKs and HO-1 activation. Estradiol in particular and ER-alpha agonists in general may promote healing of injured vascular beds by promoting EPC activity leading to more rapid endothelial recovery and capillary formation after injury.