Angiotensin receptor blockers and angiogenesis: clinical and experimental evidence

Abstract

Angiotensin II type 1 receptor antagonists [ARBs (angiotensin receptor blockers)] are indicated for BP (blood pressure)-lowering, renal protection and cardioprotection in patients unable to tolerate ACEIs (angiotensin-converting enzyme inhibitors). A recent meta-analysis revealed an association between ARBs and tumour development, possibly due to enhancement of angiogenesis. However, published evidence is conflicting on the effects of ARBs on angiogenesis or the expansion of the existing vascular network. ARBs have been shown to exert primarily anti-angiogenic effects in basic science studies of cancer, retinopathy, peripheral artery disease and some models of cardiovascular disease. In animal and cellular models of myocardial infarction and stroke, however, ARB administration has been associated with robust increases in vascular density and improved recovery. The aim of the present review is to examine the angiogenic effects of ARBs in animal and cellular models of relevant disease states, including proposed molecular mechanisms of action of ARBs and the clinical consequences of ARB use.

Candesartan Induces a Prolonged Proangiogenic Effect and Augments Endothelium-Mediated Neuroprotection after Oxygen and Glucose Deprivation: Role of Vascular Endothelial Growth Factors A and B

“…In contrast with reports from other vascular beds in which inhibition of angiogenesis was documented (Willis et al, 2011), ARB treatment was associated with increased vascular density in the brain (Munzenmaier and Greene, 2006). Long-term pretreatment with losartan (Forder et al, 2005) or valsartan (Li et al, 2008a) increased vascular density and reduced infarct volume after ischemic injury.…”

Does Outcome Reporting Bias “Cause” Cancer? Risks Associated with Hidden Data on Angiotensin Receptor Blockers

“…8 However, studies have shown that despite AT1R inhibition, tumour progression can still occur. 8 There is also evidence from animal models that unopposed AT2R stimulation (when AT1Rs are blocked by ARBs) can lead to tumour progression. 7 Although this has yet to be shown in humans, tumour progression caused by AT2R stimulation is the proposed mechanism for the increased incidence of cancer within ARB treatment groups in clinical trials.…”

“…6,7 In vitro studies have shown that agonism at both of the angiotensin receptor subtypes (AT1R and AT2R) is involved in the regulation of cellular proliferation, angiogenesis, and tumour progression. 6,[8][9][10] ARBs exert their clinical effect through ATR1 antagonism, and it is postulated that they may have anti-angiogenic properties, thereby suppressing tumour growth. 8 However, studies have shown that despite AT1R inhibition, tumour progression can still occur.…”

“…6,[8][9][10] ARBs exert their clinical effect through ATR1 antagonism, and it is postulated that they may have anti-angiogenic properties, thereby suppressing tumour growth. 8 However, studies have shown that despite AT1R inhibition, tumour progression can still occur. 8 There is also evidence from animal models that unopposed AT2R stimulation (when AT1Rs are blocked by ARBs) can lead to tumour progression.…”

“…7 Although this has yet to be shown in humans, tumour progression caused by AT2R stimulation is the proposed mechanism for the increased incidence of cancer within ARB treatment groups in clinical trials. [7][8][9] ARBs are commonly prescribed inhibitors of the renin-angiotensin-aldosterone system and are the alternative to angiotensin-converting enzyme (ACE) inhibitors in cases of allergy or intolerance. 11 Indications for ARBs approved by Health Canada are hypertension, heart failure, diabetic nephropathy, and secondary prevention of cardiovascular events.…”