From bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension

Abstract

RESISTANCE ARTERIES are vessels of ϳ100 -300 m in lumen diameter that are an important site of resistance to blood flow. Small artery-dependent increased peripheral resistance may participate in development and complications of hypertension. The degree of remodeling of small arteries has prognostic significance over a 10-yr period, with worse prognosis for hypertensive subjects with greater remodeling. In almost all hypertensive subjects, a reduction in lumen and an increase in the media-to-lumen ratio are found, without increase in its media cross section, as a result of rearrangement of smooth muscle cells and increased collagen and fibronectin. Approximately 60% of hypertensive patients exhibit endothelial dysfunction already in stage 1 hypertension. Study of human vascular smooth muscle cells and of vessels from experimental animals has demonstrated that ANG II, aldosterone, and endothelin exert remodeling effects in large measure by activation of NADPH oxidase, and to lesser degree by stimulating xanthine oxidase and mitochondrial reactive oxygen species generation. Stimulation of angiotensin type 1 (AT 1 ) receptors (AT 1 R) leads to increased reactive oxygen species in part via activation of nonreceptor tyrosine kinases such as c-src, and of PKC and phospholipase D, and thereby contributes to endothelial dysfunction by inactivating nitric oxide (NO). Treatment of hypertensive patients with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, but not ␤-blockers, corrects small artery structure and endothelial dysfunction, which may favorably affect outcome in the long term, beyond the 3-5 yr of randomized clinical trials during which most antihypertensives affect outcome similarly as long as blood pressure is well controlled.

Participation of Prostacyclin in Endothelial Dysfunction Induced by Aldosterone in Normotensive and Hypertensive Rats

“…[1][2][3][4] To date, several studies suggested that aldosterone plays a larger role than once appreciated in the regulation of vascular tone as well as in cardiovascular alterations such as endothelial dysfunction, vascular fibrosis, and inflammation, left ventricular hypertrophy, congestive heart failure, and cardiac arrhythmias. [5][6][7][8][9][10][11][12] Furthermore, aldosterone has also been shown to be involved in the pathogenesis of hypertension. [13][14][15] In general terms, endothelial dysfunction is characterized by reduced endothelium-dependent relaxations, suggesting a reduced availability of NO attributable to a reduction of NO production or enhanced NO inactivation.…”

Aldosterone: good guy or bad guy in cerebrovascular disease?

“…Many factors influence vascular structure including hormones, reactive oxygen species (ROS) and inflammatory mediators [29]. There is clear evidence that aldosterone has deleterious effects on the cardiovascular system.…”

Estudo dos mecanismos envolvidos no remodelamento de artérias de resistência de ratos hipertensos induzidos pelo tratamento com ouabaína.

“…Além disso, ele é um bem conhecido mediador de remodelamento vascular, responsável por induzir mudanças no número de células e nas proteínas da matriz extracelular (CACHOFEIRO et al, 2008;LACOLLEY;LABAT;PU et al, 2003;PUJOL, 2002;TOUYZ, 2004).…”

“…Basicamente, a capacidade do sistema renina-angiotensina em mediar o remodelamento vascular se dá pela capacidade da angiotensina II estimular vias de sinalização pró-fibróticas, em parte através da produção endógena de fatores mitogênicos tais como o TGF-β, fator de crescimento derivado de plaquetas, endotelina-1 (TOUYZ, 2005) e aldosterona (CALLERA et al, 2005), e também em parte devido à sua capacidade de induzir o aumento na produção de espécies reativas de oxigênio (ROS) (CACHOFEIRO et al, 2008;TOUYZ, 2004).…”

“…Adicionalmente, o fato do sistema renina-angiotensina possuir um importante papel na gênese de processos de remodelamento vascular (CACHOFEIRO et al, 2008;LACOLLEY;LABAT;PUJOL, 2002;MULVANY, 1995;PU et al, 2003;SCHELLING;FISCHER;GANTEN, 1991;TOUYZ, 2004), assim como os estudos que demonstram a resposta pressórica induzida pela OUA (HUANG; GANTEN; LEENEN, 2001; XAVIER et al, 2004a e c;) e a atuação tanto da COX-1 como da COX-2 no mecanismo do remodelamento vascular induzido pelo aumento da angiotensina II (BELTRÁN et al, 2009;GALÁN et al, 2011;VIRDIS et al, 2011;), pode-se supor sua provável participação, juntamente com a via da COX-2, nesse processo de remodelamento vascular induzido pela OUA.…”