Pregnancy Augments VEGF-Stimulated In Vitro Angiogenesis and Vasodilator (NO and H2S) Production in Human Uterine Artery Endothelial Cells

Abstract Context: Augmented uterine artery (UA) production of vasodilators, including nitric oxide (NO) and hydrogen sulfide (H2S), has been implicated in pregnancy-associated and agonist-stimulated rise in uterine blood flow that is rate-limiting to pregnancy health. Objective: Developing a human U...

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Published in:The journal of clinical endocrinology and metabolism 2017-07, Vol.102 (7), p.2382-2393
Main Authors: Zhang, Hong-hai, Chen, Jennifer C., Sheibani, Lili, Lechuga, Thomas J., Chen, Dong-bao
Format: Article
Language:English
Subjects:
Adult
Angiogenesis
Arteries
Blood flow
Blood Flow Velocity
Cell activation
Cell culture
Cells, Cultured - metabolism
Clinical s
Endothelial cells
Endothelial Cells - metabolism
Female
Hemodynamics
Humans
Hydrogen sulfide
Hydrogen Sulfide - metabolism
In Vitro Techniques
Muscles
Neovascularization, Physiologic - physiology
Nitric oxide
Nitric Oxide - biosynthesis
Nitric-oxide synthase
Pregnancy
Proteins
Sensitivity and Specificity
Smooth muscle
Statistical analysis
Sulfide
Uterine Artery - cytology
Uterine Artery - metabolism
Uterus
Uterus - blood supply
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - metabolism
Vasodilator Agents - metabolism
Vasodilators
Veins & arteries
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Summary:Abstract Context: Augmented uterine artery (UA) production of vasodilators, including nitric oxide (NO) and hydrogen sulfide (H2S), has been implicated in pregnancy-associated and agonist-stimulated rise in uterine blood flow that is rate-limiting to pregnancy health. Objective: Developing a human UA endothelial cell (hUAEC) culture model from main UAs of nonpregnant (NP) and pregnant (P) women for testing a hypothesis that pregnancy augments endothelial NO and H2S production and endothelial reactivity to vascular endothelial growth factor (VEGF). Design: Main UAs from NP and P women were used for developing hUAEC culture models. Comparisons were made between NP- and P-hUAECs in in vitro angiogenesis, activation of cell signaling, expression of endothelial NO synthase (eNOS) and H2S-producing enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase, and NO/H2S production upon VEGF stimulation. Results: NP- and P-hUAECs displayed a typical cobblestone-like shape in culture and acetylated low-density lipoprotein uptake, stained positively for endothelial and negatively for smooth muscle markers, maintained key signaling proteins during passage, and had statistically significant greater eNOS and CBS proteins in P- vs NP-hUAECs. Treatment with VEGF stimulated in vitro angiogenesis and eNOS protein and NO production only in P-hUEACs and more robust cell signaling in P- vs NP-hUAECs. VEGF stimulated CBS protein expression, accounting for VEGF-stimulated H2S production in hUAECs. Conclusion: Comparisons between NP- and P-hUAECs reveal that pregnancy augments VEGF-stimulated in vitro angiogenesis and NO/H2S production in hUAECs, showing that the newly established hUAEC model provides a critical in vitro tool for understanding human uterine hemodynamics. Pregnancy significantly augments VEGF-stimulated angiogenesis and vasodilator (NO and H2S) production in primary endothelial cells from the main uterine arteries of women in vitro.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2017-00437