Estrogen activates its receptors to improve lymphatic contractility through suppression of endoplasmic reticulum stress induced by hemorrhagic shock

Abstract Lymphatic contractility dysfunction is associated with the deterioration of hemorrhagic shock (HS). Endoplasmic reticulum stress (ERS) has been demonstrated to be involved in HS-induced organ injury, while estrogen alleviates HS-induced ERS and organ injury. However, whether estrogen improves lymphatic contraction through inhibition of HS-induced ERS remains unclear. We hypothesized that estrogen activation of its receptors (ERs) promoted mesenteric lymphatic contractility through suppression of HS-induced ERS in lymphatic smooth muscle cells (LSMCs). In a rodent model of HS, 17β-estradiol (E2) administration abrogated HS-induced upregulation of GRP78 in lymphatic tissues. Either E2 or ERS inhibitor 4-phenylbutyric acid (4-PBA) promoted the survival HS rats in the first 72 hours after resuscitation. E2, ER-α agonist PPT, ER-β agonist DPN, GPR30-selective agonist G-1, 4-PBA significantly enhanced the contractility of mesenteric lymphatics following HS in vivo and in vitro. In contrast, ICI 182,780 (ERα and ERβ selective inhibitor) and G-15 (GPR30-selective inhibitor) partly abolished the beneficial effects of E2. Furthermore, ERS agonist XCT-790 abolished the beneficial effects of E2, PPT, DPN, and G-1 on lymphatic contractility. Additionally, E2, PPT, DPN, and G-1 inhibited ERS, and thus ameliorate ERS agonist tunicamycin-induced hypo-contractility in primary LSMCs. Taken together, the data indicates that E2 promotes the lymphatic contractility after HS by inhibiting ERS and estrogen receptor activation mediates the beneficial effect of E2.