RhoA and ROCK mediate histamine-induced vascular leakage and anaphylactic shock

Abstract

Histamine-induced vascular leakage is an integral component of many highly prevalent human diseases, including allergies, asthma, and anaphylaxis. Yet, how histamine induces the disruption of the endothelial barrier is not well defined. By using genetically modified animal models, pharmacologic inhibitors, and a synthetic biology approach, here we show that the small GTPase RhoA mediates histamine-induced vascular leakage. Histamine causes the rapid formation of focal adherens junctions, disrupting the endothelial barrier by acting on H1R Gαq-coupled receptors, which is blunted in endothelial Gαq/11 KO mice. Interfering with RhoA and ROCK function abolishes endothelial permeability, while phospholipase Cβ plays a limited role. Moreover, endothelial-specific RhoA gene deletion prevents vascular leakage and passive cutaneous anaphylaxis in vivo, and ROCK inhibitors protect from lethal systemic anaphylaxis. This study supports a key role for the RhoA signaling circuitry in vascular permeability, thereby identifying novel pharmacological targets for many human diseases characterized by aberrant vascular leakage.

Anti-cancer effect of ursolic acid activates apoptosis through ROCK/PTEN mediated mitochondrial translocation of cofilin-1 in prostate cancer

“…Therefore it has been speculated that the formation of prostate carcinoma may be associated with overexpression of RhoA (30,31). The present study observed that prostate cells expressed ROCK/PTEN protein, and the expression of ROCK/PTEN protein in prostate carcinoma is also higher than that in BPH.…”

“…Prostate carcinoma cells may express RhoA protein, and the expression of RhoA protein in prostate carcinoma is higher than that in benign prostatic hyperplasia (BPH) (30). Therefore it has been speculated that the formation of prostate carcinoma may be associated with overexpression of RhoA (30,31).…”

Small Rho GTPase-mediated actin dynamics at endothelial adherens junctions

“…53 This has been shown to be essential for permeability induced by thrombin, VEGF, histamine and TNF-a. [54][55][56] In contrast, RhoA activation in response to angiopoietin-1 has been described to result in cell-cell junction stabilization. This endothelial barrier-protective effect of RhoA in response to angiopoietin-1 is mediated via the Rho-effector mDia, inducing actin polymerization.…”

Leukocyte transendothelial migration: A local affair

“…55,56 Also, both SHP2 and Ga signaling can result in RhoA activation. 57,58 How then can these events occur specifically at one Tyr residue of the same protein with an almost opposite outcome? Although more detailed research should be performed to fully clarify this point, but we speculate that the signals require more proteins within one complex that can act in a very local and transient manner.…”