Aldosterone mediates actions of the renin-angiotensin-aldosterone system inducing hypertension, oxidative stress, and vascular inflammation. Recently, we showed that angiotensin II-induced hypertension and vascular damage are mediated at least in part by macrophages and T-helper effector lymphocytes. Adoptive transfer of suppressor T-regulatory lymphocytes (Tregs) prevented angiotensin II action. We hypothesized that Treg adoptive transfer would blunt aldosterone-induced hypertension and vascular damage. Thirteen to 15-week-old male C57BL/6 mice were injected intravenously at 1-week intervals with 3×10(5) CD4(+)CD25(+) cells (representing Treg) or control CD4(+)CD25(-) cells and then infused or not for 14 days with aldosterone (600 μg/kg per day, SC) while receiving 1% saline to drink. Aldosterone induced a small but sustained increase in blood pressure (P<0.001), decreased vasodilatory responses to acetylcholine by 66% (P<0.001), increased both media:lumen ratio (P<0.001) and media cross-sectional area of resistance arteries by 60% (P<0.05), and increased NADPH oxidase activity 2-fold in aorta (P<0.001), kidney and heart (P<0.05), and aortic superoxide production. As well, aldosterone enhanced aortic and renal cortex macrophage infiltration and aortic T-cell infiltration (all P<0.05), and tended to decrease Treg in the renal cortex. Treg adoptive transfer prevented all of the vascular and renal effects induced by aldosterone. Adoptive transfer of CD4(+)CD25(-) cells exacerbated aldosterone effects except endothelial dysfunction and increases in media:lumen ratio of resistance arteries. Thus, Tregs suppress aldosterone-mediated vascular injury, in part through effects on innate and adaptive immunity, suggesting that aldosterone-induced vascular damage could be prevented by an immunomodulatory approach.

Abstract-Angiotensin type 2 receptor-mediated effects of angiotensin II appear to counteract many of the effects mediated via the angiotensin type 1 receptor. Compound 21 (C21), a selective angiotensin type 2 receptor agonist, has demonstrated beneficial effects on cardiac function after myocardial infarction in rodents. We hypothesized that C21 alone or in combination with an angiotensin type 1 receptor antagonist would blunt the development of hypertension and vascular damage in stroke-prone spontaneously hypertensive rats. Six-week-old stroke-prone spontaneously hypertensive rats received C21 (1 mg/kg per day), the angiotensin type 1 receptor antagonist losartan (10 mg/kg per day), C21 plus losartan, or vehicle PO for 6 weeks. Systolic blood pressure was lower in losartan and C21-losartan combination groups (PϽ0.001). Endotheliumdependent relaxation was enhanced (PϽ0.001) in the C21-losartan combination group at lower acetylcholine concentrations. C21 or C21-losartan combination reduced vascular stiffness, aortic medial and myocardial interstitial collagen content, and aortic fibronectin (PϽ0.05). C21 and losartan decreased the expression of 2 genes associated with cardiac hypertrophy, myosin heavy chain-␤ (myh7) by 30 to 50%, and ␣-skeletal muscle actin by 30% to 35% (PϽ0.05). C21-losartan combination caused an additional 40% reduction in myh7 compared with C21 (PϽ0.01). Aortic superoxide generation was reduced equally by the 3 treatments (PϽ0.001). Monocyte/macrophage infiltration in the aorta and kidney (PϽ0.001) and T-lymphocyte infiltration in the renal cortex (PϽ0.05) were lowered similarly by the 3 treatments. These data suggest that C21 alone or in combination with losartan may improve endothelial function and vascular composition and mechanics by reducing oxidative stress, collagen content, fibronectin, and inflammatory cell infiltration in stroke-prone spontaneously hypertensive rats. hronic hypertension results in vascular remodeling and inflammation, endothelial dysfunction, and accelerated development of atherosclerosis. 1,2 Of the many factors implicated in hypertensive vascular remodeling, angiotensin (Ang) II, the main effector hormone of the renin-Ang-aldosterone system, seems to be one of the most important. 3 Ang II exerts its effects by binding to 2 membrane-bound, G proteincoupled receptors, Ang II type 1 (AT 1 R) and type 2 receptors (AT 2 R). Most well-known effects of Ang II that contribute to unfavorable vascular remodeling and consequent hypertensive complications are mediated via AT 1 R, whereas those exerted via AT 2 R are less well known and appear to counteract many of its effects exerted via AT 1 R. 4,5 AT 2 Rmediated effects seem to exert vasculoprotective actions via vasodilation, NO production, 6 -8 and apoptosis and inhibition of growth and fibrosis. 5,9,10 Beneficial vascular effects of AT 1 R blockade have been at least partially attributed to unopposed AT 2 R stimulation. 7,11,12

Objective— Endothelin (ET)-1 plays a role in vascular reactive oxygen species production and inflammation. ET-1 has been implicated in human atherosclerosis and abdominal aortic aneurysm (AAA) development. ET-1 overexpression exacerbates high-fat diet–induced atherosclerosis in apolipoprotein E −/− ( Apoe −/− ) mice. ET-1–induced reactive oxygen species and inflammation may contribute to atherosclerosis progression and AAA development. Approach and Results— Eight-week-old male wild-type mice, transgenic mice overexpressing ET-1 selectively in endothelium (eET-1), Apoe −/− mice, and eET-1/ Apoe −/− mice were fed high-fat diet for 8 weeks. eET-1/ Apoe −/− had a 45% reduction in plasma high-density lipoprotein ( P <0.05) and presented ≥2-fold more aortic atherosclerotic lesions compared with Apoe −/− ( P <0.01). AAAs were detected only in eET-1/ Apoe −/− (8/21; P <0.05). Reactive oxygen species production was increased ≥2-fold in perivascular fat, media, or atherosclerotic lesions in the ascending aorta and AAAs of eET-1/ Apoe −/− compared with Apoe −/− ( P <0.05). Monocyte/macrophage infiltration was enhanced ≥2.5-fold in perivascular fat of ascending aorta and AAAs in eET-1/ Apoe −/− compared with Apoe −/− ( P <0.05). CD4 + T cells were detected almost exclusively in perivascular fat (3/6) and atherosclerotic lesions (5/6) in ascending aorta of eET-1/ Apoe −/− ( P <0.05). The percentage of spleen proinflammatory Ly-6C hi monocytes was enhanced 26% by ET-1 overexpression in Apoe −/− ( P <0.05), and matrix metalloproteinase-2 was increased 2-fold in plaques of eET-1/ Apoe −/− ( P <0.05) compared with Apoe −/− . Conclusions— ET-1 plays a role in progression of atherosclerosis and AAA formation by decreasing high-density lipoprotein, and increasing oxidative stress, inflammatory cell infiltration, and matrix metalloproteinase-2 in perivascular fat, vascular wall, and atherosclerotic lesions.

BackgroundPersons experiencing homelessness and vulnerable housing or those with lived experience of homelessness have worse health outcomes than individuals who are stably housed. Structural violence can dramatically affect their acceptance of interventions. We carried out a systematic review to understand the factors that influence the acceptability of social and health interventions among persons with lived experience of homelessness.MethodsWe searched through eight bibliographic databases and selected grey literature sources for articles that were published between 1994 and 2019. We selected primary studies that reported on the experiences of homeless populations interacting with practitioners and service providers working in permanent supportive housing, case management, interventions for substance use, income assistance, and women- and youth-specific interventions. Each study was independently assessed for its methodological quality. We used a framework analysis to identify key findings and used the GRADE-CERQual approach to assess confidence in the key findings.FindingsOur search identified 11,017 citations of which 35 primary studies met our inclusion criteria. Our synthesis highlighted that individuals were marginalized, dehumanized and excluded by their lived homelessness experience. As a result, trust and personal safety were highly valued within human interactions. Lived experience of homelessness influenced attitudes toward health and social service professionals and sometimes led to reluctance to accept interventions. Physical and structural violence intersected with low self-esteem, depression and homeless-related stigma. Positive self-identity facilitated links to long-term and integrated services, peer support, and patient-centred engagement.ConclusionsIndividuals with lived experience of homelessness face considerable marginalization, dehumanization and structural violence. Practitioners and social service providers should consider anti-oppressive approaches and provide, refer to, or advocate for health and structural interventions using the principles of trauma-informed care. Accepting and respecting others as they are, without judgment, may help practitioners navigate barriers to inclusiveness, equitability, and effectiveness for primary care that targets this marginalized population.

Mmp2 knockout impaired Ang II-induced vascular injury but not BP elevation. BM transplantation revealed a role for immune cells in Ang II-induced BP elevation, and for both vascular and immune cell MMP2 in Ang II-induced endothelial dysfunction.

Inducible Pparγ inactivation in VSMCs exacerbated Ang II-induced vascular remodelling and endothelial dysfunction via enhanced vascular oxidative stress and inflammation, revealing the protective role of VSMC PPARγ in angiotensin II-induced vascular injury.

E ndothelin (ET)-1 is one of the most potent vasoconstrictor peptides.1 ET is produced by endothelial cells (ECs) and by other cell types.1,2 The effects of ET-1 are mediated by 2 G-coupled receptors: ET type A (ET A ) and B (ET B ) receptors. ET-1 secreted by EC acts in paracrine fashion on ET A and ET B receptors on underlying vascular smooth muscle cells to induce contraction and growth. It also acts in autocrine fashion on EC ET B receptors to release vasodilator nitric oxide (NO) and prostacyclin. ET B receptors also play a role in ET-1 clearance and mediate natriuresis by acting on the kidney.ET-1 has been implicated in the development of hypertension and vascular damage.3,4 Plasma ET-1 is elevated in patients with essential hypertension, 5 particularly in moderate-to-severe hypertension 6 and in hypertension associated with other disorders, such as chronic kidney disease, metabolic syndrome, and diabetes mellitus.3 ET-1 expression is also increased in salt-dependent models of experimental hypertension such as deoxycorticosterone acetate-salt hypertension, 7 spontaneous hypertensive rats treated with deoxycorticosterone acetate and salt, 8 stroke-prone spontaneous hypertensive rat, 9 and in Dahl salt-sensitive rats. 10 In these rodents, enhanced ET-1 expression is associated with increased vascular oxidative stress, endothelial dysfunction, and hypertrophic vascular remodeling. However, direct evidence that ET-1 may directly raise blood pressure (BP) has been difficult to obtain. Genetic manipulation of ET-1 gene (Edn1) expression levels has yielded contradictory results on the role of ET-1 on BP regulation. Homozygous Edn1 null mice were not viable and presented craniofacial malformation. 11 On the contrary, Edn1 haploinsufficiency (Edn1 +/-) paradoxically caused hypertension. Endothelial-restricted Edn1 knockout generated by crossing mice with floxed Edn1 exon 2 (Edn1 Flox/Flox) with mice expressing Cre recombinase under the transcriptional control of the endothelium-specific angiopoietin-1 receptor (Tek also known as Tie2) promoter, caused Abstract-The mechanisms of blood pressure regulation by endothelin-1 produced by endothelial cells are complex and still unclear. Transgenic mice with endothelium-restricted human endothelin-1 (EDN1) overexpression presented vascular damage but no significant change in blood pressure, which could be because of adaptation to life-long exposure to elevated endothelin-1 levels. We now generated a tamoxifen-inducible endothelium-restricted EDN1 overexpressing transgenic mouse (ieET-1) using Cre/loxP technology. Sixteen days after tamoxifen treatment, ieET-1 mice presented ≥10-fold increase in plasma endothelin-1 (P<0.01) and ≥20 mm Hg elevation in systolic blood pressure (P<0.01), which could be reversed by atrasentan (P<0.05). Endothelin-1 overexpression did not cause vascular or kidney injury or changes in kidney perfusion or function. However, endothelin type A and B receptor expression was differentially regulated in the mesenteric arteries and the kidney. Our resu...

VSMC Pparγ inactivation exaggerates ET-1-induced vascular injury, supporting a protective role for PPARγ in hypertension through modulation of pro-oxidant and proinflammatory pathways. Paradoxically, ET-1 overexpression preserved endothelial function in smPparγ-/- mice, presumably by enhancing nitric oxide through stimulation of endothelin type B receptors.