Sex Differences in Angiotensin II Hypertension

Sullivan, Jennifer C.

doi:10.1007/978-1-4939-3213-9_5

Cited by 5 publications

(7 citation statements)

References 111 publications

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“…28, 29 In contrast, we found that the direct effect of Ang II on endothelial function was not sex-dependent in E-V290M mice. Although that finding is somewhat surprising, there are studies in humans and animal models where effects of Ang II were sex-independent, and also cases where Ang II caused greater vascular responses in women than in men.…”

Section: Discussioncontrasting

confidence: 71%

Genetic Interference With Endothelial PPAR-γ (Peroxisome Proliferator–Activated Receptor-γ) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1–7

Silva

Kinzenbaw

et al. 2017

Hypertension

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Pharmacological activation of peroxisome proliferator-activated receptor-γ (PPARγ) protects the vasculature. Much less is known regarding the cell specific impact of PPARγ when driven by endogenous ligands. Recently, we found that endothelial PPARγ protects against angiotensin II (Ang II)-induced endothelial dysfunction. Here, we explored that concept further examining if effects were sex-dependent along with underlying mechanisms. We studied mice expressing a human dominant negative mutation in PPARγ driven by the endothelial specific vascular cadherin promoter (E-V290M), using non-transgenic (non-Tg) littermates as controls. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation of carotid arteries from non-Tg and E-V290M mice. Incubation of isolated arteries with Ang II (1 nmol/L) overnight had no effect in non-Tg, but reduced responses to acetylcholine by about 50% in male and female E-V290M mice (p<0.05). Endothelial function in E-V290M mice was restored to normal by inhibitors of superoxide (tempol), NADPH oxidase (VAS-2870), Rho kinase (Y-27632), ROCK2 (SLX-2119), NF-κB (NEMO-binding domain peptide), or IL-6 (neutralizing antibody). In addition, we hypothesized that PPARγ may influence the angiotensin 1-7 (Ang 1-7) arm of the renin-angiotensin system. In the basilar artery, dilation to Ang 1-7 was selectively reduced in E-V290M mice by >50% (p<0.05), an effect reversed by Y-27632. Thus, effects of Ang II are augmented by interference with endothelial PPARγ through sex-independent mechanisms, involving oxidant-inflammatory signaling and Rho kinase (ROCK2). The study also provides the first evidence that endothelial PPARγ interacts with Ang 1-7 responses. These critical roles for endothelial PPARγ have implications for pathophysiology and therapeutic approaches for vascular disease.

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Section: Discussioncontrasting

confidence: 71%

Genetic Interference With Endothelial PPAR-γ (Peroxisome Proliferator–Activated Receptor-γ) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1–7

Silva

Kinzenbaw

et al. 2017

Hypertension

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“…This phenomenon may not be an anomaly as a similar trend is seen in other rodent experiments (68,69). It is possible that ANG II-induced hypertension has sexually distinct mechanisms that lead to temporal variations (65). We observe the quantitative, but not the qualitative, difference between the sexes in our model simulation of ANG II infusion, thus suggesting that additional sexually distinct mechanisms need to be incorporated in our model.…”

Section: Discussionsupporting

confidence: 83%

Sex-specific computational models for blood pressure regulation in the rat

Ahmed

2020

American Journal of Physiology-Renal Physiology

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Renal hemodynamics play a critical role in blood pressure regulation, while renal autoregulatory mechanisms maintain kidney function for varying blood pressure. Computational models have been developed of the cardiovascular system to simulate blood pressure regulation in humans, including the seminal model by Guyton et al. (Ann Rev Physiol 1972). Although the Guyton model and its many variants represent mechanisms for renal autoregulation, they appear to fail to adequately maintain glomerular filtration rate for a sufficiently wide range of blood pressure. Additionally, while such human models have clinical values in that they can be used to assess the effects and reveal mechanisms of hypertensive therapeutic treatments, rodent models would be more useful in assisting the interpretation of animal experiments. Finally, despite well‐known sexual dimorphism in blood pressure regulation, all published models are gender neutral Given these observations, the goal of this project is to develop the first sex‐specific computational models of blood pressure regulation for the rat. The resulting models represent the interplay between cardiovascular function, renal hemodynamics, and kidney function. They also include the actions of the renal sympathetic nerve activity and the renin‐angiotensin‐aldosterone system. We applied the models to investigate the cardiovascular effects of antihypertensive treatments including diuretics, angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blocker (ARB), and of nonsteroidal anti‐inflammatory drugs (NSAIDs). Simulations were conducted to identify risks factors for acute kidney injury following the administration of a combination of these treatments. Support or Funding Information This research was supported by the Canada 150 Research Chair program and by the National Institutes of Health: National Institute of Diabetes and Digestive and Kidney Diseases, grant R01DK106102. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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“…As suggested by experts in the area, experiments in this initial study were performed using adult male and female mice with intact gonads (Morselli et al, 2016). Some cardiovascular effects of Ang II are sex-dependent (Faraci et al, 2006;Girouard et al, 2008;Sullivan, 2015). In the current study, we found that direct effects of Ang II on endothelial function was not sex-dependent.…”

Section: Sex-dependent Effects Of Ang IIsupporting

confidence: 54%

“…Consistent with previous studies, Ang II produced endothelial dysfunction in the current experiments. An advantage of the model used is the testing of direct effects of Ang II on the vessel wall without confounders such as differences in arterial pressure that occur in some models when Ang II is administered systemically (Sullivan, 2015). The current model phenocopies effects of chronic systemic treatment with Ang II on endothelial function (Johnson et al, 2013; Li et al, 2016; Schrader et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II‐induced endothelial dysfunction: Impact of sex, genetic background, and rho kinase

Kinzenbaw

Langmack

Faraci

2022

Physiological Reports

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The renin‐angiotensin system (RAS) contributes to vascular disease with multiple cardiovascular risk factors including hypertension. As a major effector within the RAS, angiotensin II (Ang II) activates diverse signaling mechanisms that affect vascular biology. Despite the impact of such vascular pathophysiology, our understanding of the effects of Ang II in relation to the function of endothelial cells is incomplete. Because genetic background and biological sex can be determinants of vascular disease, we performed studies examining the direct effects of Ang II using carotid arteries from male and female mice on two genetic backgrounds, C57BL/6J and FVB/NJ. Although FVB/NJ mice are much less susceptible to atherosclerosis than C57BL/6J, the effects of Ang II on endothelial cells in FVB/NJ are poorly defined. Overnight incubation of isolated arteries with Ang II (10 nmol/L), impaired endothelial function in both strains and sexes by approximately one‐half ( p < 0.05). To examine the potential mechanistic contribution of Rho kinase (ROCK), we treated arteries with SLX‐2119, an inhibitor with high selectivity for ROCK2. In both male and female mice of both strains, SLX‐2119 largely restored endothelial function to normal, compared to vessels treated with vehicle. Thus, Ang II‐induced endothelial dysfunction was observed in both FVB/NJ and C57BL/6J mice. This effect was sex‐independent. In all groups, effects of Ang II were reversed by inhibition of ROCK2 with SLX‐2119. These studies provide the first evidence that ROCK2 may be a key contributor to Ang II‐induced endothelial dysfunction in both sexes and in mouse strains that differ in relation to other major aspects of vascular disease.

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Sex Differences in Angiotensin II Hypertension

Cited by 5 publications

References 111 publications

Genetic Interference With Endothelial PPAR-γ (Peroxisome Proliferator–Activated Receptor-γ) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1–7

Genetic Interference With Endothelial PPAR-γ (Peroxisome Proliferator–Activated Receptor-γ) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1–7

Sex-specific computational models for blood pressure regulation in the rat

Angiotensin II‐induced endothelial dysfunction: Impact of sex, genetic background, and rho kinase

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