Abstract 067: Unexpected Actions of the Endothelial-EP 4 Receptor for PGE 2 to Promote Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Ting Yang ◽  
Marcela Herrera ◽  
Matthew A Sparks ◽  
Michael Manning ◽  
Beverly H Koller ◽  
...  
Keyword(s):  
Ductus Arteriosus ◽  
Major Effect ◽  
Salt Sensitivity ◽  
Ang Ii ◽  
Conditional Deletion ◽  
Receptor Isoforms ◽  
Ep Receptor ◽  
Natal Mortality ◽  
Opposing Effect

Prostaglandin E2 (PGE 2 ) is a major prostanoid produced by the kidney with vasodilator and natriuretic actions and its actions are mediated by four distinct E-prostanoid (EP) receptor isoforms: EP 1 -EP 4 . The EP 4 receptor (EP 4 R) has multiple actions that could impact blood pressure (BP) by triggering macula densa stimulation of renin, inducing vasodilation, and inhibiting epithelial sodium transport. Accordingly, we examined the role of EP 4 R on BP regulation by generating EP 4 R-deficient mice. Because deletion of EP 4 R in utero causes peri-natal mortality due to persistent patent ductus arteriosus, we carried out conditional deletion using an EP 4 flox/flox mouse line. We first generated mice completely lacking EP 4 R in all tissues (TBKO) using a tamoxifen-inducible transgene driving Cre expression in all tissues. Resting mean arterial pressure (MAP) measured by radiotelemetry tended to be elevated in TBKOs compared to controls (106±2 vs 111±2 mmHg; p=0.06). In addition TBKOs showed exaggerated salt sensitivity and enhanced hypertensive response to chronic Ang II infusion compared to controls (MAP increase: 25±3 vs. 37±2 mmHg; p<0.05). To determine whether altered BP responses in the TBKOs were due to elimination of EP 4 R-depedent actions in vascular smooth muscle cells (VSMCs) or in endothelial cells (ECs), we generated mice lacking EP 4 R in VSMCs (SMKO) or ECs (ECKO) using EP 4 flox/flox and transgenic mice with tamoxifen-inducible expression of Cre limited to VSMCs or ECs. Resting MAP in SMKO mice was significantly reduced compared to controls (109±1 vs. 104±2 mmHg; p<0.05), but salt sensitivity and Ang II-dependent hypertension were unaffected. Although no statistically significant differences in baseline MAP or salt sensitivity were observed between ECKOs and controls, the hypertensive response to AngII infusion was significantly reduced in ECKOs (MAP increase: 31±3 vs 24±2 mmHg; p<0.05). In summary, our work suggests a complex role for PGE 2 acting via its EP 4 R in BP regulation, with a major effect to promote resistance to hypertension, apparent in the TBKOs. However, we have also uncovered an unexpected and opposing effect of EP 4 R in endothelium to promote hypertension.

Role of endothelin ETB receptor activation in angiotensin II-induced hypertension: effects of salt intake

2001 ◽  
Vol 281 (5) ◽  
pp. H2218-H2225 ◽  
Author(s):  
Jennifer R. Ballew ◽  
Gregory D. Fink
Keyword(s):  
Arterial Pressure ◽  
Receptor Antagonist ◽  
Salt Intake ◽  
Receptor Activation ◽  
Salt Sensitivity ◽  
Male Rats ◽  
Ang Ii ◽  
High Salt Intake ◽  
Induced Hypertension

We showed recently that endothelin (ET)A receptors are involved in the salt sensitivity of ANG II-induced hypertension. The objective of this current study was to characterize the role of endothelin ETB receptor activation in the same model. Male rats on fixed normal (2 meq/day) or high (6 meq/day) salt intake received a continuous intravenous infusion of ANG II or salt only for 15 days. During the middle 5 days of the infusion period, rats were given either the selective ETB receptor antagonist A-192621 or the nonselective endothelin receptor antagonist A-182086 (both at 24 mg · kg−1 · day−1intra-arterially). Infusion of ANG II caused a greater rise in arterial pressure in rats on high-salt intake. The administration of A-192621 increased arterial pressure further in all rats. The chronic hypertensive effect of A-192621 was not significantly affected by salt intake or ANG II. The administration of A-182086 lowered arterial pressure chronically only in rats on normal salt intake receiving ANG II. Thus the salt sensitivity of ANG II-induced hypertension is not caused by changes in ETB receptor function.

ANG II-induced hypertension and the role of the area postrema during normal and increased dietary salt

2007 ◽  
Vol 292 (1) ◽  
pp. H694-H700 ◽  
Author(s):  
David B. Nahey ◽  
John P. Collister
Keyword(s):  
Arterial Pressure ◽  
Area Postrema ◽  
Salt Sensitivity ◽  
High Salt ◽  
Dietary Sodium ◽  
Ang Ii ◽  
Dietary Salt ◽  
Full Development ◽  
Induced Hypertension

It has been shown that the area postrema (AP) plays a role in the development of certain types of chronic angiotensin II (ANG II)-induced hypertension in the rat but is not of great importance in the salt sensitivity of arterial pressure. It has recently been proposed, however, that elevated sodium levels may exacerbate the hypertensive effects of ANG II, which by itself dramatically affects salt sensitivity, by acting at sodium-sensing neurons in certain circumventricular organs of the brain. Thus the interactions of ANG II, sodium, and the central nervous system remain to be fully understood. The purpose of this study was to examine the role of the AP in ANG II-induced hypertension during periods of normal and elevated dietary salt. We hypothesized that an intact AP was necessary for the full development of hypertension under chronic ANG II infusion and that its role would be pronounced during periods of increased dietary sodium. To test this, male Sprague-Dawley rats underwent ablation of the area postrema (APx, n = 6) or sham operation (sham, n = 6). After 3 wk of recovery, rats were instrumented with radiotelemetry transducers for constant blood pressure and heart rate monitoring and venous catheters for vehicle infusion. After a 3-day control period of 0.9% saline infusion (7 ml/day) and 0.4% dietary sodium, a 10-day period of ANG II infusion (10 ng·kg−1·min−1) was begun, immediately followed by a second 10-day period during which rats were fed a 4.0% sodium diet. By day 6 of ANG II infusion, mean arterial pressure (MAP) in APx rats had increased to 139 ± 4 mmHg, whereas MAP in sham rats had increased to 126 ± 3 mmHg. This difference was found to be significant and continued through day 1 of the high-salt period, after which MAP of the two groups had risen to similar levels. On day 9 of high salt, MAP was again observed to be significantly higher (162 ± 1 mmHg) in APx rats when compared with sham rats (147 ± 4 mmHg.) These results do not support the hypothesis that the AP is necessary for the full development of ANG II-induced hypertension at normal or elevated levels of dietary sodium.

scholarly journals A possible role of neuropeptide Y, agouti-related protein and leptin receptor isoforms in hypothalamic programming by perinatal feeding in the rat

Diabetologia ◽  
2004 ◽  
Vol 48 (1) ◽  
pp. 140-148 ◽  
Author(s):  
M. L�pez ◽  
L. M. Seoane ◽  
S. Tovar ◽  
M. C. Garc�a ◽  
R. Nogueiras ◽  
...  
Keyword(s):  
Neuropeptide Y ◽  
Leptin Receptor ◽  
Related Protein ◽  
Receptor Isoforms ◽  
Agouti Related Protein

scholarly journals Hypoxia and Mitochondrial Dysfunction in Pregnancy Complications

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 405 ◽  
Author(s):  
Xiang-Qun Hu ◽  
Lubo Zhang
Keyword(s):  
Pregnancy Complications ◽  
Intrauterine Growth Restriction ◽  
Animal Studies ◽  
Major Effect ◽  
Causative Role ◽  
Therapeutic Approaches ◽  
Maternal Complications ◽  
Mitochondrial Ros ◽  
Subsequent Risk

Hypoxia is a common and severe stress to an organism’s homeostatic mechanisms, and hypoxia during gestation is associated with significantly increased incidence of maternal complications of preeclampsia, adversely impacting on the fetal development and subsequent risk for cardiovascular and metabolic disease. Human and animal studies have revealed a causative role of increased uterine vascular resistance and placental hypoxia in preeclampsia and fetal/intrauterine growth restriction (FGR/IUGR) associated with gestational hypoxia. Gestational hypoxia has a major effect on mitochondria of uteroplacental cells to overproduce reactive oxygen species (ROS), leading to oxidative stress. Excess mitochondrial ROS in turn cause uteroplacental dysfunction by damaging cellular macromolecules, which underlies the pathogenesis of preeclampsia and FGR. In this article, we review the current understanding of hypoxia-induced mitochondrial ROS and their role in placental dysfunction and the pathogenesis of pregnancy complications. In addition, therapeutic approaches selectively targeting mitochondrial ROS in the placental cells are discussed.

Effects of long-term chloroquine administration on the natural history of aortic aneurysms in mice

2015 ◽  
Vol 93 (8) ◽  
pp. 641-648 ◽  
Author(s):  
Azza Ramadan ◽  
Mark D. Wheatcroft ◽  
Adrian Quan ◽  
Krishna K. Singh ◽  
Fina Lovren ◽  
...  
Keyword(s):  
Natural History ◽  
Thrombus Formation ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
Suprarenal Aorta ◽  
History Of ◽  
Categorical Distribution

Autophagy regulates cellular homeostasis and integrates the cellular pro-survival machinery. We investigated the role of autophagy in the natural history of murine abdominal aortic aneurysms (AAA). ApoE−/− mice were implanted with saline- or angiotensin II (Ang-II)-filled miniosmotic pumps then treated with either the autophagy inhibitor chloroquine (CQ; 50 mg·(kg body mass)–1·day–1, by intraperitoneal injection) or saline. Ang-II-elicited aneurysmal expansion of the suprarenal aorta coupled with thrombus formation were apparent 8 weeks later. CQ had no impact on the incidence (50% for Ang-II compared with 46.2% for Ang-II + CQ; P = NS) and categorical distribution of aneurysms. The markedly reduced survival rate observed with Ang-II (57.1% for Ang-II compared with 100% for saline; P < 0.05) was unaffected by CQ (61.5% for Ang-II + CQ; P = NS compared with Ang-II). CQ did not affect the mean maximum suprarenal aortic diameter (1.91 ± 0.19 mm for Ang-II compared with 1.97 ± 0.21 mm for Ang-II + CQ; P = NS). Elastin fragmentation, collagen accumulation, and smooth muscle attrition, which were higher in Ang-II-treated mice, were unaffected by CQ treatment. Long-term CQ administration does not affect the natural history and prognosis of experimental AAA, suggesting that global loss of autophagy is unlikely to be a causal factor in the development of aortic aneurysms. Manipulation of autophagy as a mechanism to reduce AAA may need re-evaluation.

Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression

2004 ◽  
Vol 287 (5) ◽  
pp. H1957-H1966 ◽  
Author(s):  
Faina Schwartz ◽  
Arvi Duka ◽  
Irena Duka ◽  
Jing Cui ◽  
Haralambos Gavras
Keyword(s):  
Gene Expression ◽  
Cardiac Remodeling ◽  
Unknown Function ◽  
Mouse Heart ◽  
Ang Ii ◽  
Coordinate Regulation ◽  
Transcriptional Changes ◽  
Novel Targets ◽  
Molecular Circuitry

Although the central role of ANG II in cardiovascular homeostasis is well appreciated, the molecular circuitry of its many actions is not completely understood. With the use of serial analysis of gene expression to assess global transcriptional changes in the heart of mice after continuous 7-day ANG II administration, we identified patterns of gene expression indicative of cardiac remodeling, including coordinate regulation of genes previously described in a context of processes associated with hypertrophy and fibrosis. In addition, we discovered several novel ANG II targets, including characterized genes of known function, recently annotated genes of unknown function, and the putative genes not yet present in current databases. The serial analysis of gene expression approach to assess the role of ANG II presented in this report provides new venues for inquiries into ANG II-mediated cardiac function.

Abstract 070: AntagomiR-762 Prevents Angiotensin II Induced Aortic Fibrosis and Stiffening

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Kim Ramil C Montaniel ◽  
Jing Wu ◽  
Matthew R Bersi ◽  
Liang Xiao ◽  
Hana A Itani ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Organ Damage ◽  
Matrix Proteins ◽  
Locked Nucleic Acid ◽  
Ang Ii ◽  
End Organ Damage ◽  
Acid Inhibitor ◽  
Vascular Stiffening ◽  
Aortic Stiffening

We and others have shown that hypertension (HTN) is associated with a striking deposition of collagen in the vascular adventitia. This causes vascular stiffening, which increases pulse wave velocity and contributes to end-organ damage. Through a screen of vascular microRNAs (miRNAs), we found that miR-762 is the most upregulated miRNA in mice with angiotensin II (Ang II)-induced HTN. qRT-PCR confirmed that miR-762 is upregulated 6.35±1.22 (p=0.03) fold in aortas of Ang II-infused mice compared with controls. This was a direct effect of Ang II, as miR-762 upregulation was not eliminated by lowering blood pressure with hydralazine and hydrochlorothiazide and was increased only 2-fold in DOCA salt HTN. To study the role of miR-762 in HTN, we administered a locked nucleic acid inhibitor of miR-762 (antagomiR-762). AntagomiR-762 administration did not alter the hypertensive response to Ang II, yet it normalized stress-strain relationships and aortic energy storage that occurs in systole (Table). Further studies showed that antagomiR-762 dramatically affected vascular matrix proteins, reducing mRNA for several collagens and fibronectin and dramatically upregulating collagenases MMP1a, 8 and 13 (Table). Thus, miR-762 has a major role in modulating vascular stiffening and its inhibition dramatically inhibits pathological fibrosis, enhances matrix degradation and normalizes aortic stiffness. AntagomiR-762 might represent a new approach to prevent aortic stiffening and its consequent end-organ damage.

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