Angiotensin System In Hypertension Research Articles

Angiotensin II Regulation of Proliferation, Differentiation, and Engraftment of Hematopoietic Stem Cells.

Emerging evidence indicates that differentiation and mobilization of hematopoietic cell are critical in the development and establishment of hypertension and hypertension-linked vascular pathophysiology. This, coupled with the intimate involvement of the hyperactive renin-angiotensin system in hypertension, led us to investigate the hypothesis that chronic angiotensin II (Ang II) infusion affects hematopoietic stem cell (HSC) regulation at the level of the bone marrow. Ang II infusion resulted in increases in hematopoietic stem/progenitor cells (83%) and long-term HSC (207%) in the bone marrow. Interestingly, increases of HSCs and long-term HSCs were more pronounced in the spleen (228% and 1117%, respectively). Furthermore, we observed higher expression of C-C chemokine receptor type 2 in these HSCs, indicating there was increased myeloid differentiation in Ang II-infused mice. This was associated with accumulation of C-C chemokine receptor type 2(+) proinflammatory monocytes in the spleen. In contrast, decreased engraftment efficiency of GFP(+) HSC was observed after Ang II infusion. Time-lapse in vivo imaging and in vitro Ang II pretreatment demonstrated that Ang II induces untimely proliferation and differentiation of the donor HSC resulting in diminished HSC engraftment and bone marrow reconstitution. We conclude that (1) chronic Ang II infusion regulates HSC proliferation, mediated by angiotensin receptor type 1a, (2) Ang II accelerates HSC to myeloid differentiation resulting in accumulation of C-C chemokine receptor type 2(+) HSCs and inflammatory monocytes in the spleen, and (3) Ang II impairs homing and reconstitution potentials of the donor HSCs. These observations highlight the important regulatory roles of Ang II on HSC proliferation, differentiation, and engraftment.

Androgen-induced hypertension in angiotensinogen deficient mice: Role of 20-HETE and EETS

20-HETE is a potent inducer of endothelial ACE in vitro and administration of lisinopril or losartan attenuates blood pressure in models of 20-HETE-dependent hypertension. The present study was undertaken to further define the relationship between 20-HETE and the renin–angiotensin system in hypertension using an angiotensinogen-deficient mouse (Agt+/−). Treatment of male AGT+/− with 5α-dihydrotestosterone (DHT) increased systolic BP from 102±2 to 125±3mmHg; in comparison, the same treatment raised BP in wild type (WT) from 110±2 to 138±2mmHg. DHT increased vascular 20-HETE levels in AGT+/− and WT from 1.5±0.7 and 2.1±0.6 to 13.0±2.0 and 15.8±4.0ng/mg, respectively. Concurrent treatment with the 20-HETE antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) prevented the increases in BP in both AGT+/− and WT mice. Administration of 20-HEDE at the peak of the DHT-induced BP increase (12 days) reduced BP to basal levels after 48h. Interestingly, basal levels of renal microvascular EETs were higher in AGT+/− compared to WT (55.2±9.7 vs 20.0±4.1ng/mg) and treatment of AGT+/− with DHT decreased the levels of EETs (28.4±5.1ng/mg). DHT-mediated changes in vascular EET level were not observed in WT mice. Vascular Cyp4a12 and ACE protein levels were increased in both AGT+/− and WT by 30–40% and decreased with concomitant administration of 20-HEDE. Lisinopril was as effective as 20-HEDE in preventing DHT-mediated increases in BP in both AGT+/− and WT mice. This study substantiates our previous findings that the RAS plays an important role in 20-HETE-mediated hypertension. It also proposes a novel interaction between 20-HETE and EETs.

In Brief

Angiotensin-converting enzyme (ACE) regulates blood pressure and cardiac function by its role in converting the biologically inactive angiotensin I into the vasoconstrictor angiotensin II. The recent discovery of ACE2, a related protease that promotes the generation of vasodilator products from the same precursor, angiotensin I, has raised new questions about the role of the renin–angiotensin system in hypertension and cardiac function. A new study published in Nature compared blood pressure, cardiac function and angiotensin II levels in ACE knockout mice and ACE2 knockout mice. ACE knockout mice had low blood pressure but normal cardiac function, whereas the opposite was observed in ACE2 knockout mice: they displayed normal blood pressure and impaired cardiac contractility. The double knockout (ACE−/−, ACE2−/−) showed a phenotype similar to that of the ACE single knockout, indicating that ablation of ACE rescues the abnormalities in cardiac function induced by the absence of ACE2. [Crackower, M.A. et al. (2002) Nature 417, 822–827] AB

Contrasting effects of angiotensin type 1 and 2 receptors on nitric oxide release under pressure.

This study was designed to test the hypothesis that increased pressure itself could cause endothelial dysfunction and lead to decreased nitric oxide (NO) release, partly through effects on the tissue renin angiotensin system in hypertension. Cultured endothelial cells (ECs) isolated from the aortas of WKY rats were continuously exposed to a pressure of 150 mmHg in a CO2 incubator for 72 h using a pressure system, and the NOx (NO2 and NO3) and angiotensin II (Ang II) concentrations in the supernatant were measured. An Ang II type 1 receptor (AT1R) antagonist (losartan) and an Ang II type 2 receptor (AT2R) antagonist (PD123319) were added to the medium. The expression of AT1R and AT2R mRNAs was also examined. Pressure loading significantly decreased the NO release from ECs. Concomitant administration of losartan restored NO release to the level before the application of pressure (p<0.001). This effect of losartan was blocked by simultaneous administration of PD123319, bradykinin type 2 receptor antagonist, and NO synthase inhibitor (p<0.05). The Ang II concentration was increased by pressure and was further increased by losartan. The gene expression of AT1R was not changed by pressure, but AT2R mRNA was increased almost 2-fold. These results indicate that high pressure itself attenuates NO release from ECs, and that losartan improves NO release by activating the bradykinin system via AT2R stimulation. In addition, the increase of AT2R gene expression in ECs during exposure to pressure may compensate for the reduction of NO.

The developmental increase of the AT1A, but not the AT1B, receptor MRNA level at the preoptic area in spontaneously hypertensive rats

To determine the possible involvement of the central angiotensin system in hypertension, the angiotensin II type-1 receptor subtype mRNA levels in the preoptic area (POA) and hypothalamus were measured by means of a reverse-transcriptase/polymerase chain reaction in spontaneously hypertensive rats (SHR), and the results were then compared with the findings in age-matched normotensive Wistar-Kyoto rats (WKY). In 4-week-old (prehypertensive stage) and 7-week-old (evolving stage) SHR, the AT1A and AT1B receptor subtype mRNA levels in the POA and hypothalamus did not show any significant difference between the SHR and WKY. However, in the 16-week-old SHR (hypertensive stage), AT1A receptor subtype mRNA at POA was approximately 2-fold higher than in the WKY, while the AT1B receptor subtype mRNA showed no difference. On the other hand, neither the AT1A nor the AT1B mRNA level at the hypothalamus were different between the 16-week-old SHR and WKY. These results suggest that the AT1A mRNA level, but not the AT1B mRNA level, increases in the POA in hypertensive stage of SHR and the increase may therefore be related in some way to the state of hypertension.

Developmental differences of angiotensinogen mRNA in the preoptic area between spontaneously hypertensive and age-matched Wistar-Kyoto rats

In order to know the possible involvement of the central angiotensin system in hypertension, angiotensinogen mRNA (AomRNA) levels of eight discrete brain areas were measured by Northern blot hybridization analysis in the spontaneously hypertensive rats (SHR), compared with those in age-matched normotensive Wistar-Kyoto rats (WKY). In 16-week-old SHR (hypertensive stage), AomRNA levels in the preoptic area (POA), but not in the ventromedial hypothalamus, lateral hypothalamus and mammillary body, among the hypothalamic nuclei, were higher (approximate 50%) than in WKY. There were no differences in other brain areas, such as the striatum, septum, amygdala and cerebellum between both the strains. The AomRNA levels in POA were already higher (38%) in 4-week-old SHR (prehypertensive stage) without significance, and the difference was augmented (82%) in 7-week-old SHR (evolving stage). These results suggest that the developmental changes of AomRNA levels at POA may be related in some aspect to hypertension process.