Integrative Physiology B lood vessels consist of 2 major cell types, endothelial and mural cells, such as pericytes and vascular smooth muscle cells (VSMC), which surround the endothelium. Regulator of G-protein signaling 5 (RGS5) is expressed in mural cells and has emerged as a crucial modulator of vascular pathology in cancer. For instance, we have demonstrated that RGS5 is highly upregulated in angiogenic tumor pericytes.1 Loss of RGS5 results in pericyte maturation and normalization of tumor vasculature.2,3 Moreover, we showed a crucial role for RGS5 in regulating vascular barrier function in tumors and in brain capillaries during ischemia, and also provided the first genetic evidence that RGS5 is involved in vascular wall remodeling in adults. 2A striking feature of RGS5 expression is its dynamic nature in various physiological and pathological states, which indicates a role in adaptive processes. 1,[4][5][6] This is consistent with RGS5 being a member of the extended family of RGS molecules, which are modulators of G-protein-coupled receptors (GPCRs). G-protein signaling pathways rely on rapid on-off kinetics, and RGS molecules act as GTPaseactivating proteins (GAP) for heterotrimeric G proteins and, as such, regulate duration and intensity of signaling events. They contain a highly conserved carboxyl-terminal RGS domain that confers the catalytic function for active Gα subunits. Members of the R4/B subfamily, which include, among others, RGS 2, 4, and 5, are the smallest RGS Original received September 21, 2012; revision received January 7, 2013; accepted January 9, 2013. In December 2012, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.5 days.
Preeclampsia is a systemic vascular disorder of pregnancy and is associated with increased sensitivity to angiotensin II (AngII) and hypertension. The cause of preeclampsia remains unknown. We identified the role of regulator of G protein (heterotrimeric guanine nucleotide-binding protein) signaling 5 (RGS5) in blood pressure regulation during pregnancy and preeclampsia. RGS5 expression in human myometrial vessels is markedly suppressed in gestational hypertension and/or preeclampsia. In pregnant RGS5-deficient mice, reduced vascular RGS5 expression causes gestational hypertension by enhancing vascular sensitivity to AngII. Further challenge by increasing AngII results in preeclampsia-like symptoms, namely, more severe hypertension, proteinuria, placental pathology, and reduced birth weight. In pregnant heterozygote null mice, treatment with peroxisome proliferator-activated receptor (PPAR) agonists normalizes vascular function and blood pressure through effects on RGS5. These findings highlight a key role of RGS5 at the interface between AngII and PPAR signaling. Because preeclampsia is refractory to current standard therapies, our study opens an unrecognized and urgently needed opportunity for treatment of gestational hypertension and preeclampsia.
The intracellular second messenger, cyclic guanosine monophosphate (cGMP), a soluble guanylate cyclase (GC) product, is a primary mechanism for the transduction of a nitric oxide (NO)-initiated signal in the central nervous system. NO is produced from L-arginine by neuronal nitric oxide synthase (NOS), which is found in sympathetic preganglionic neurons of the intermediolateral cell column. This suggests the possibility that NO is a modulator of sympathetic nervous activity (SNA) through a cGMP-mediated mechanism. The aim of this study was to determine the effects of intrathecally injected membrane-permeant 8-bromo-cGMP and 1H (10 μl, 1, 3, 10, 30, 100 μM). A dose-effect relationship (1 μM to 100 μM) was also established (EC 50 = 6.03 μM). During continuous haemorrhage, MAP was maintained in animals injected with 8-Br-cGMP, relative to the control group. Although no change in baseline MAP was observed as a result of intrathecal ODQ injection (10 μl, 100 mM), a greater rate of fall in MAP was observed during haemorrhage. Injecting L-arginine (10, 100, 1000 μM, 10 μl) showed a pressor effect that was consistent with the effect of the downstream messenger, cGMP. Furthermore, its pressor effect was blocked by ODQ pre-administration. The results indicate that cGMP increases blood pressure, and thus suggest that cGMP increases SNA. This supports the hypothesis that the sympathoexcitatory effects of spinal delivery of NO are mediated by a cGMP-dependent mechanism.
Both rat strain and anaesthetic influence HR responses to haemorrhage, and some anaesthetics appear less suitable than others for studies of haemodynamic responses in rats. There was evidence of an additional compensatory mechanism that operates at advanced levels of hypotension in the rat.
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