Advantages in Wound Healing Process in Female Mice Require Upregulation A-Mediated Angiogenesis under the Stimulation of 17β-Estradiol.

Estrogenic steroids and adenosine A receptors promote the wound healing and angiogenesis processes. However, so far, it is unclear whether estrogen may regulate the expression and pro-angiogenic activity of A receptors. Using in vivo analyses, we showed that female wild type (WT) mice have a more rapid wound healing process than female or male A-deficient mice (AKO) mice. We also found that pulmonary endothelial cells (mPEC) isolated from female WT mice showed higher expression of A receptor than mPEC from male WT mice. mPEC from female WT mice were more sensitive to A-mediated pro-angiogenic response, suggesting an ER and A crosstalk, which was confirmed using cells isolated from AKO. In those female cells, 17β-estradiol potentiated A-mediated cell proliferation, an effect that was inhibited by selective antagonists of estrogen receptors (ER), ERα, and ERβ. Therefore, estrogen regulates the expression and/or pro-angiogenic activity of A adenosine receptors, likely involving activation of ERα and ERβ receptors. Sexual dimorphism in wound healing observed in the AKO mice process reinforces the functional crosstalk between ER and A receptors.