Advantages in Wound Healing Process in Female Mice Require Upregulation A(2A)-Mediated Angiogenesis under the Stimulation of 17β-Estradiol

Estrogenic steroids and adenosine A(2A) 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(2A) 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(2A)-deficient mice (A(2A)KO) mice. We also found that pulmonary endothelial cells (mPEC) isolated from female WT mice showed higher expression of A(2A) receptor than mPEC from male WT mice. mPEC from female WT mice were more sensitive to A(2A)-mediated pro-angiogenic response, suggesting an ER and A(2A) crosstalk, which was confirmed using cells isolated from A(2A)KO. In those female cells, 17β-estradiol potentiated A(2A)-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(2A) adenosine receptors, likely involving activation of ERα and ERβ receptors. Sexual dimorphism in wound healing observed in the A(2A)KO mice process reinforces the functional crosstalk between ER and A(2A) receptors.