Angiotensin II Type 1A Receptors in Vascular Smooth Muscle Cells Do Not Influence Aortic Remodeling in Hypertension

Sparks, Matthew A.; Parsons, Kelly; Stegbauer, Johannes; Gurley, Susan B.; Vivekanandan-Giri, Anuradha; Fortner, Christopher N.; Snouwaert, Jay; Raasch, Eric W.; Griffiths, Robert; Haystead, Timothy A.J.; Le, Thu H.; Pennathur, Subramaniam; Koller, Beverly H.; Coffman, Thomas M.

doi:10.1161/hypertensionaha.110.165274

Cited by 56 publications

(63 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, we studied the vascular NO resistance in resistant arterioles (cremaster muscle arterioles) because they are largely involved in blood pressure regulation and in ANG II hypertensive effect (24) whereas most of previous investigations focused on conduit vessels (aorta and arteries). Indeed, remodeling of the arteriolar wall and changes in smooth muscle reactivity is associated with vascular resistance during the development of hypertension (12,33).…”

Section: Discussionmentioning

confidence: 99%

Soluble guanylyl cyclase is a target of angiotensin II-induced nitrosative stress in a hypertensive rat model

Crassous

Couloubaly

Huang

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Soluble guanylyl cyclase is a target of angiotensin II-induced nitrosative stress in a hypertensive rat model. Am J Physiol Heart Circ Physiol 303: H597-H604, 2012. First published June 22, 2012; doi:10.1152/ajpheart.00138.2012 by activating soluble guanylyl cyclase (sGC) is involved in vascular homeostasis via induction of smooth muscle relaxation. In cardiovascular diseases (CVDs), endothelial dysfunction with altered vascular reactivity is mostly attributed to decreased NO bioavailability via oxidative stress. However, in several studies, relaxation to NO is only partially restored by exogenous NO donors, suggesting sGC impairment. Conflicting results have been reported regarding the nature of this impairment, ranging from decreased expression of one or both subunits of sGC to heme oxidation. We showed that sGC activity is impaired by thiol S-nitrosation. Recently, angiotensin II (ANG II) chronic treatment, which induces hypertension, was shown to generate nitrosative stress in addition to oxidative stress. We hypothesized that S-nitrosation of sGC occurs in ANG II-induced hypertension, thereby leading to desensitization of sGC to NO hence vascular dysfunction. As expected, ANG II infusion increases blood pressure, aorta remodeling, and protein S-nitrosation. Intravital microscopy indicated that cremaster arterioles are resistant to NO-induced vasodilation in vivo in anesthetized ANG II-treated rats. Concomitantly, NO-induced cGMP production decreases, which correlated with S-nitrosation of sGC in hypertensive rats. This study suggests that S-nitrosation of sGC by ANG II contributes to vascular dysfunction. This was confirmed in vitro by using A7r5 smooth muscle cells infected with adenoviruses expressing sGC or cysteine mutants: ANG II decreases NO-stimulated activity in the wild-type but not in one mutant, C516A. This result indicates that cysteine 516 of sGC mediates ANG II-induced desensitization to NO in cells. nitric oxide resistance; vascular dysfunction; oxidative stress; hypertension SOLUBLE GUANYLYL CYCLASE (sGC) is the main receptor for nitric oxide (NO) and the enzyme responsible for the conversion of GTP into cGMP. As such, the NO-receptor sGC is crucially involved in the physiology of the cardiovascular system by modulating vessel tone. Indeed, mice lacking this receptor are hypertensive (5). Oxidative stress is associated with cardiovascular diseases (CVDs) such as hypertension, atherosclerosis, and diabetes. Most oxidative CVDs are accompanied by endothelial dysfunction and impaired vascular reactivity with decreased NO bioavailability. Nonetheless, it should be pointed out that oxidative stress affects as well the smooth muscle cell (SMC) layers where sGC is expressed. It has been reported that reactive oxygen species (ROS) alter sGC expression and activity (19,25,29). We (21) have previously shown that in vitro and in vivo S-nitrosation of sGC impairs its ability to be activated by NO. In particular, we established that infusion of low therapeutic doses of nitroglycerin in rats for 3 days i...

show abstract

Section: Discussionmentioning

confidence: 99%

Soluble guanylyl cyclase is a target of angiotensin II-induced nitrosative stress in a hypertensive rat model

Crassous

Couloubaly

Huang

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…20,21 To delete the Agtr1a flox allele in collecting duct, we took advantage of an existing transgenic line expressing Cre recombinase in the collecting duct under the control of a Hoxb7 promoter (Hoxb7-Cre) 22 that had been back-crossed multiple generations onto the 129/SvEv background. We verified the pattern of Cre expression by crossing the Hoxb7-Cre mouse with a double-fluorescence reporter mouse (mT/mG).…”

Section: Generation Of Mice Lacking At 1a Receptors In Collecting Ductmentioning

confidence: 99%

“…20 Membrane-targeted tdTomato (mT)/membrane-targeted EGFP (mG) mice with loxP sites flanking the membrane-targeted dtTomato cassette followed by an N-terminal membrane-tagged version of EGFP were purchased from the Jackson Laboratory and crossed with the two Cre recombinase transgenic lines. mTmG mice normally express red fluorescence protein in all tissues.…”

Section: Experimental Micementioning

confidence: 99%

AT1 Receptors in the Collecting Duct Directly Modulate the Concentration of Urine

Stegbauer

Gurley

Sparks

et al. 2011

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

Mice lacking AT 1 angiotensin receptors have an impaired capacity to concentrate the urine, but the underlying mechanism is unknown. To determine whether direct actions of AT 1 receptors in epithelial cells of the collecting duct regulate water reabsorption, we used Cre-Loxp technology to specifically eliminate AT 1A receptors from the collecting duct in mice (CD-KOs). Although levels of AT 1A receptor mRNA in the inner medulla of CD-KO mice were significantly reduced, their kidneys appeared structurally normal. Under basal conditions, plasma and urine osmolalities and urine volumes were similar between CD-KO mice and controls. The increase in urine osmolality in response to water deprivation or vasopressin administration, however, was consistently attenuated in CD-KO mice. Similarly, levels of aquaporin-2 protein in inner and outer medulla after water deprivation were significantly lower in CD-KO mice compared with controls, despite its normal localization to the apical membrane. In summary, these results demonstrate that AT 1A receptors in epithelial cells of the collecting duct directly modulate aquaporin-2 levels and contribute to the concentration of urine. The renin-angiotensin system (RAS) has myriad physiologic actions including the regulation of water homeostasis through modulation of thirst, vasopressin release, and urinary concentrating mechanisms. 1-5 Pharmacologic and gene targeting studies suggest that these actions are mediated primarily by type 1 (AT 1 ) receptors. 5,6 Mice have two AT 1 receptor isoforms, AT 1A and AT 1B , which are highly homologous. The AT 1A receptor is predominantly expressed in most tissues including the kidney and is the murine homologue to the single human AT 1 receptor. Mice completely lacking AT 1A receptors develop polyuria and an impaired urinary concentrating capacity, with an attenuated increase in urine osmolality after water deprivation or vasopressin administration. 5,6 On the other hand, gene targeting studies have demonstrated distinct roles for the AT 1B receptor in the regulation of thirst. 7,8 Nonetheless, the precise mechanisms and cellular targets of AT 1A receptors responsible for regulating urine concentration have not been precisely documented.Evidence from in vivo and in vitro studies suggests that the collecting duct is an important target for the modulation of water handling by the RAS. For example, in cell culture experiments, it

show abstract

“…To determine the extent of vascular remodeling associated with the Ang II infusion, medial thickness of thoracic aortic sections was measured by morphometry as described. 24 As shown in Figure 6, no difference was seen in medial thickness of the thoracic aorta between controls and TP-SMKOs that did not receive Ang II infusions (P=NS), suggesting that the absence of TP receptors in VSMCs does not significantly impact normal development and structure of the aorta. After 4 weeks of Ang II infusion, there was significant remodeling of the aorta in control mice reflected by an ≈84% increase in medial thickness from 43±2 to 79±7 µm (P<0.0005).…”

Section: Hypertensive End-organ Damage Is Diminished In Mice Lacking mentioning

confidence: 85%

Thromboxane Receptors in Smooth Muscle Promote Hypertension, Vascular Remodeling, and Sudden Death

Sparks

Makhanova²,

Griffiths³

et al. 2013

Hypertension

Self Cite

View full text Add to dashboard Cite

Abstract-The prostanoid thromboxane A 2 has been implicated to contribute to the pathogenesis of many cardiovascular diseases, including hypertension. To study the role of vascular thromboxane-prostanoid (TP) receptors in blood pressure regulation, we generated mice with cell-specific deletion of TP receptors in smooth muscle using Cre/Loxp technology. We crossed the KISM22α-Cre transgenic mouse line expressing Cre recombinase in smooth muscle cells with a mouse line bearing a conditional allele of the Tbxa2r gene (Tp flox ). In KISM22α-Cre + Tp flox/flox (TP-SMKO) mice, TP receptors were efficiently deleted from vascular smooth muscle cells. In TP-SMKOs, acute vasoconstrictor responses to the TP agonist U46619 were attenuated to a similar extent in both the peripheral and renal circulations. Yet, acute vascular responses to angiotensin II were unaffected at baseline and after chronic angiotensin II administration. Infusion of high-dose U46619 caused circulatory collapse and death in a majority of control mice but had negligible hemodynamic effects in TPSMKOs, which were completely protected from U46619-induced sudden death. Baseline blood pressures were normal in TP-SMKOs. However, the absence of TP receptors in vascular smooth muscle cells was associated with significant attenuation of angiotensin II-induced hypertension and diminished vascular remodeling. This was also associated with reduced urinary thromboxane production after chronic angiotensin II. Thus, TP receptors in vascular smooth muscle cells play a major role in mediating the actions of thromboxane A 2 in TP agonist-induced shock, hypertension, and vascular remodeling of the aorta.

show abstract

Angiotensin II Type 1A Receptors in Vascular Smooth Muscle Cells Do Not Influence Aortic Remodeling in Hypertension

Cited by 56 publications

References 72 publications

Soluble guanylyl cyclase is a target of angiotensin II-induced nitrosative stress in a hypertensive rat model

Soluble guanylyl cyclase is a target of angiotensin II-induced nitrosative stress in a hypertensive rat model

AT1 Receptors in the Collecting Duct Directly Modulate the Concentration of Urine

Thromboxane Receptors in Smooth Muscle Promote Hypertension, Vascular Remodeling, and Sudden Death

Contact Info

Product

Resources

About