Estrogen Enhances the Microvascular Reactivity Through RhoA-ROCK Pathway in Female Mice During Hemorrhagic Shock

Abstract

Vascular hypo-reactivity plays a critical role inducing organ injury during hemorrhagic shock. 17b-estradiol (E2) can induce vasodilation to increase blood flow in various vascular beds. This study observed whether E2 can restore vascular hypo-reactivity induced by hemorrhagic shock, and whether E2 effects are associated with RhoA-Rho kinase (ROCK)-myosin light chain kinase phosphatase (MLCP) pathway. The hemorrhagic shock model (40 AE 2 mm Hg for 1 h, resuscitation for 4 h) was established in ovary intact sham operation (OVI), ovariectomized (OVX), and OVX plus E2 supplement female mice. Intestinal microvascular loop was used to assess blood flow in vivo, mRNA expression and vascular reactivity in vitro. Hemorrhagic shock significantly reduced norepinephrine microvascular reactivity. Decreased microvascular reactivity was exacerbated by OVX and reversed by E2 supplement. U-46619 (RhoA agonist) increased microvascular reactivity, and C3 transferase (an ADP ribosyl transferase that selectively induces RhoA ribosylation) or Y-27632 (ROCK inhibitor) inhibited sham mice microvascular reactivity. Similarly, U-46619 increased microvascular reactivity in OVI and OVX mice following hemorrhagic shock, which was abolished by Y-27632 or concomitant incubation of okadaic acid (OA) (MLCP inhibitor) and Y-27632. In OVX plus E2 supplement mice with hemorrhagic shock, Y-27632 inhibited microvascular reactivity, which was abolished by concomitant U-46619 application. Lastly, hemorrhagic shock remarkably decreased intestinal loop blood flow, RhoA and ROCK mRNA expressions in vascular tissues in OVX females, but not in OVI females, which were reversed by E2 supplement. These results indicate that estrogen improves microvascular reactivity during hemorrhagic shock, and RhoA-ROCK signaling pathway may mediate E2 effects.

Roles of the RhoA-ROCK Signaling Pathway in the Endothelial H2S Production and Vasodilation in Rat Cerebral Arteries

“…However, the interaction of the RhoA-ROCK signaling pathway with H 2 S is unclear in rat cerebral arteries. As shown in Figure 1b, compared to the control group, CSE and 3-MST protein expression in rat cerebrovascular ECs was obviously reduced by the RhoA agonist U 46619 32 (100 nmol/ L), and CSE but not 3-MST protein expression was significantly increased by the RhoA inhibitor C3 transferase 33 (C3TF, 1.0 μg/mL). U 46619 remarkably reduced but C3TF increased basic or ACh-increased H 2 S content in rat cerebrovascular ECs compared with that in the control group or the ACh group (Figure 1d).…”

Estrogen Alleviates Posthemorrhagic Shock Mesenteric Lymph-Mediated Lung Injury Through Autophagy Inhibition

“…Recent studies showed that ethinyl estradiol sulfate, an estrogenic derivative, blunted hemorrhagic shock induced-multiple harmful outcomes in rat and swine, and showed a broad prospect of clinical application (30,31). Our previous studies have demonstrated that E2 prolonged the survival time and normalized CD4 + T lymphocyte function of rats after hemorrhagic shock (19) and attenuated hemorrhagic shock-induced vascular hyporeactivity in mice (25). In this study, we applied the small animal pulmonary function assay system and confirmed that E2 treatment improved the pulmonary function evidenced by these indices including RI, FRC, PEF, and IC of hemorrhagic shock rats.…”

“…After pulmonary function measurement, the intestinal loop blood flow was recorded in all rats as previously described (25). Briefly, the rat received an abdominal operation at room temperature to expose the intestinal loop of about 15 cm upward of the cecum, which is tiled in a circle.…”

Autophagy Is Involved in Stellate Ganglion Block Reversing Posthemorrhagic Shock Mesenteric Lymph-Mediated Vascular Hyporeactivity

“…It should be pointed out that vascular contractility following hemorrhagic shock was studied by various methods, such as pressor response to NE in vivo (Zhao et al, 2012 ; Li et al, 2014 ), a reduced percentage of vascular diameter after NE administration in vivo (Li et al, 2014 ), and isolated vascular contractile response to gradient concentrations of NE in vitro (Duan et al, 2020 ; Yue et al, 2021 ). While all these methods clarified that hemorrhagic shock induced vascular hyporeactivity in various ways.…”