Novel role of mechanosensitive AT1B receptors in myogenic vasoconstriction

Blodow, Stephanie; Schneider, Holger; Storch, Ursula; Wizemann, Richard; Forst, A. W.; Gudermann, Thomas; Schnitzler, Michael Mederos y

doi:10.1007/s00424-013-1372-3

Cited by 35 publications

(52 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…13,15,21 Moreover, there is evidence that overexpression of AT 1 Rs causes proteinuria, 22 and AT 1 R antagonists and angiotensin-converting enzyme inhibitors are protective for podocytes and can improve proteinuria. 23,24 Therefore, we analyzed the role of G q/11 PCRs as potential mechanosensors in podocytes.…”

Section: G Q/11 -Pcrs Are Not Mechanosensors In Podocytesmentioning

confidence: 99%

“…10 Because the podocin homolog MEC-2 is part of a mechanosensitive multiprotein ion channel complex in Caenorhabditis elegans, it was suggested that TRPC6 in complex with other slit-membrane proteins (including podocin) could form a mechanosensitive ion channel complex. 2 Of note, in our previous studies, G q/11 -proteincoupled receptors (G q/11 PCRs) and not TRPC6 channels shaped up as mechanosensors in vascular smooth muscle cells 13,15 contributing to myogenic vasoconstriction. There is still growing evidence for an inherent mechanosensitivity of G-protein-coupled receptors (GPCRs) in other tissues and organs (summarized by Storch et al 16 ).…”

mentioning

confidence: 93%

See 1 more Smart Citation

Podocyte Purinergic P2X4 Channels Are Mechanotransducers That Mediate Cytoskeletal Disorganization

Forst¹,

Olteanu²,

Mollet

et al. 2016

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

Podocytes are specialized, highly differentiated epithelial cells in the kidney glomerulus that are exposed to glomerular capillary pressure and possible increases in mechanical load. The proteins sensing mechanical forces in podocytes are unconfirmed, but the classic transient receptor potential channel 6 (TRPC6) interacting with the MEC-2 homolog podocin may form a mechanosensitive ion channel complex in podocytes. Here, we observed that podocytes respond to mechanical stimulation with increased intracellular calcium concentrations and increased inward cation currents. However, TRPC6-deficient podocytes responded in a manner similar to that of control podocytes, and mechanically induced currents were unaffected by genetic inactivation of TRPC1/3/6 or administration of the broad-range TRPC blocker SKF-96365. Instead, mechanically induced currents were significantly decreased by the specific P2X purinoceptor 4 (P2X 4 ) blocker 5-BDBD. Moreover, mechanical P2X 4 channel activation depended on cholesterol and podocin and was inhibited by stabilization of the actin cytoskeleton. Because P2X 4 channels are not intrinsically mechanosensitive, we investigated whether podocytes release ATP upon mechanical stimulation using a fluorometric approach. Indeed, mechanically induced ATP release from podocytes was observed. Furthermore, 5-BDBD attenuated mechanically induced reorganization of the actin cytoskeleton. Altogether, our findings reveal a TRPC channel-independent role of P2X 4 channels as mechanotransducers in podocytes.

show abstract

Section: G Q/11 -Pcrs Are Not Mechanosensors In Podocytesmentioning

confidence: 99%

mentioning

confidence: 93%

Podocyte Purinergic P2X4 Channels Are Mechanotransducers That Mediate Cytoskeletal Disorganization

Forst¹,

Olteanu²,

Mollet

et al. 2016

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Investigating both murine AT 1 R isoforms, we recently found that mechanosensitive AT 1B but not AT 1A receptors are key elements for mechanosensation in VSMC mediating myogenic tone. 5 However, myogenic tone was not completely lost in AT 1B gene-deficient arteries or after blockade of AT 1 Rs with candesartan or losartan, suggesting that other signaling pathways might participate in myogenic tone. The aim of this study was to analyze the total effect of AT 1A and AT 1B receptors on myogenic tone by investigating AT 1A/1B double gene-deficient (AT 1A/1B −/− ) mice and to discover novel candidate mechanosensors in the vasculature.…”

mentioning

confidence: 99%

“…Recently, angiotensin II AT 1 receptors (AT 1 Rs) emerged as mechanosensors in VSMCs mediating myogenic tone and in cardiac myocytes inducing cardiac hypertrophy independent of agonist. [5][6][7][8][9] Numerous other G-protein-coupled receptors, such as the bradykinin B 2 , the endothelin ET A , the parathyroid hormone type 1, the histamine H 1 , the muscarinic M 5 , and the formyl peptide 1, are discussed as mechanosensors. 10 For some of these receptors, physiological roles emerged, for example, as sensors of fluid shear stress in endothelial cells, for retraction of pseudopods in neutrophils or for bone growth.…”

mentioning

confidence: 99%

Cysteinyl Leukotriene 1 Receptors as Novel Mechanosensors Mediating Myogenic Tone Together With Angiotensin II Type 1 Receptors—Brief Report

Storch

Blodow

Gudermann

et al. 2015

ATVB

Self Cite

View full text Add to dashboard Cite

Objective-Myogenic vasoconstriction is mediated by vascular smooth muscle cells of resistance arteries sensing mechanical stretch. Angiotensin II AT 1 receptors and in particular AT 1B Rs in murine vascular smooth muscle cells have been characterized as mechanosensors that cannot fully account for myogenic vasoconstriction observed. Therefore, we aimed at uncovering novel vascular mechanosensors by expression profiling and functional characterization of candidate proteins. Approach and Results-Analyzing myogenic tone of isolated murine mesenteric arteries of AT 1A and AT 1B receptor double gene-deficient (AT 1A/1B −/− ) mice ex vivo, we observed a decreased myogenic tone at high intraluminal pressures and an unexpected hyper-reactivity at low intraluminal pressures because of upregulation of cysteinyl leukotriene 1 receptors (CysLT 1 Rs). Pharmacological blockade of CysLT 1 Rs with pranlukast significantly reduced myogenic tone not only in AT 1A/1B −/− but also in wild-type arteries. In wild-type arteries, additional blockade of angiotensin II AT 1 receptors with candesartan resulted in an additive reduction of myogenic tone. Furthermore, calcium imaging experiments were performed with fura-2-loaded human embryonic kidney 293 cells overexpressing CysLT 1 Rs and with isolated mesenteric vascular smooth muscle cells. Hypo-osmotically induced membrane stretch provoked calcium transients that were significantly reduced by pranlukast. Incubations of isolated mesenteric vascular smooth muscle cells with the 5-lipoxygenase inhibitor zileuton had no effect. Furthermore, the G q/11 -protein inhibitor YM 254890 profoundly reduced myogenic tone to the same extent as induced by the application of pranlukast plus candesartan. Conclusions-Here, we identify a novel, hitherto unappreciated role of CysLT 1 Rs in vascular regulation. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results CysLT 1 Rs Together With AT 1 Rs Mediate Myogenic Vasoconstriction via G q/11 -ProteinsTo analyze myogenic tone of AT 1A/1B −/− mice ex vivo, we performed pressure myography of isolated murine mesenteric arteries (IMMAs) from AT 1A/1B −/− and wild-type (WT) mice. Unexpectedly, AT 1A/1B −/− arteries were hyper-reactive with significantly increased myogenic vasoconstriction at a premyogenic pressure range from 20 to 70 mm Hg ( Figure 1A). Only at higher pressures >100 mm Hg, myogenic tone was significantly reduced as expected. Figure 1B shows exemplary vessel diameter time courses at incremental pressure levels. Because vascular hyper-reactivity might be caused by compensatory upregulation of other proteins, gene expression profiling was performed showing that among all G-proteincoupled receptors, only CysLT 1 Rs were significantly enriched in AT 1A/1B −/− IMMAs as confirmed by quantitative reverse-transcriptase-polymerase chain reaction ( Figure 1C). Therefore, we pursued a pharmacological approach and applied pranlukast, a selective CysLT 1 R antagonist, at maximally inhibitory concentrations. Admini...

show abstract

“…6, 8, 25, 26 The current experiments were aimed at extending this to investigate how mechanosensitive GPCR-mediated myogenic responsiveness is regulated. Specifically, using isolated arteriolar VSMCs and cannulated arterioles, the present studies focused on RGS5-mediated regulation of the AT 1 R during mechanical (ligand-independent) or Ang II (ligand-dependent) activation.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Type 1 Receptor Mechanoactivation Involves RGS5 (Regulator of G Protein Signaling 5) in Skeletal Muscle Arteries

Hong

Nourian

et al. 2017

Hypertension

View full text Add to dashboard Cite

Studies suggest that arteriolar pressure-induced vasoconstriction can be initiated by G protein-coupled receptors, including the angiotensin II type 1 receptor (AT1R). This raises the question, are such mechanisms regulated by negative feedback? The present studies examined whether regulators of G-protein signaling proteins (RGS) in vascular smooth muscle cells (VSMCs) are co-localized with the AT1R when activated by mechanical stress or angiotensin II (Ang II) and if this modulates AT1R-mediated vasoconstriction. To determine if activation of the AT1R recruits RGS5, an in situ proximity ligation assay (PLA) was performed in primary cultures of cremaster muscle arteriolar VSMCs treated with Ang II or hypotonic solution in the absence or presence of candesartan (an AT1R blocker). PLA results revealed a concentration-dependent increase in trafficking/translocation of RGS5 towards the activated AT1R, which was attenuated by candesartan. In intact arterioles, knockdown of RGS5 enhanced constriction to Ang II and augmented myogenic responses to increased intraluminal pressure. Myogenic constriction was attenuated to a higher degree by candesartan in RGS5 siRNA-transfected arterioles, consistent with RGS5 contributing to down regulation of AT1R-mediated signaling. Further, translocation of RGS5 was impaired in VSMCs of spontaneously hypertensive rats (SHR). This is consistent with dysregulated (RGS5-mediated) AT1R signaling that could contribute to excessive vasoconstriction in hypertension. In intact vessels, candesartan reduced myogenic vasoconstriction to a greater extent in SHR compared to controls. Collectively, these findings suggest that AT1R activation results in translocation of RGS5 towards the plasma membrane, limiting AT1R-mediated vasoconstriction through its role in Gq/11 protein-dependent signaling.

show abstract

Novel role of mechanosensitive AT1B receptors in myogenic vasoconstriction

Cited by 35 publications

References 35 publications

Podocyte Purinergic P2X4 Channels Are Mechanotransducers That Mediate Cytoskeletal Disorganization

Podocyte Purinergic P2X4 Channels Are Mechanotransducers That Mediate Cytoskeletal Disorganization

Cysteinyl Leukotriene 1 Receptors as Novel Mechanosensors Mediating Myogenic Tone Together With Angiotensin II Type 1 Receptors—Brief Report

Angiotensin II Type 1 Receptor Mechanoactivation Involves RGS5 (Regulator of G Protein Signaling 5) in Skeletal Muscle Arteries

Contact Info

Product

Resources

About