Abstract
Renin–angiotensin systems produce angiotensin II (Ang II) and angiotensin 1-7 (Ang 1-7), which are able to induce opposite effects on circulation. This study in vivo assessed the effects induced by Ang II or Ang 1-7 on rat pial microcirculation during hypoperfusion–reperfusion, clarifying the mechanisms causing the imbalance between Ang II and Ang 1-7. The fluorescence microscopy was used to quantify the microvascular parameters. Hypoperfusion and reperfusion caused vasoconstriction, disruption of blood–brain barrier, reduction of capillary perfusion and an increase in reactive oxygen species production. Rats treated with Ang II showed exacerbated microvascular damage with stronger vasoconstriction compared to hypoperfused rats, a further increase in leakage, higher decrease in capillary perfusion and marker oxidative stress. Candesartan cilexetil (specific Ang II type 1 receptor (AT1R) antagonist) administration prior to Ang II prevented the effects induced by Ang II, blunting the hypoperfusion–reperfusion injury. Ang 1-7 or ACE2 activator administration, preserved the pial microcirculation from hypoperfusion–reperfusion damage. These effects of Ang 1-7 were blunted by a Mas (Mas oncogene-encoded protein) receptor antagonist, while Ang II type 2 receptor antagonists did not affect Ang 1-7-induced changes. In conclusion, Ang II and Ang 1-7 triggered different mechanisms through AT1R or MAS receptors able to affect cerebral microvascular injury.
Highlights
IntroductionThe renin–angiotensin–system (RAS) can fine tune the amount of angiotensin II (Ang II) acting on microvascular networks
Cerebral circulation has been extensively studied under the pathophysiological conditions of ischemia and reperfusion; in particular, previous data obtained using in vitro models indicate that angiotensin II (Ang II) affects cerebral microcirculation through the activation of angiotensin II Type 1 receptor (AT1 R) during ischemia–reperfusion injury [1,2,3,4]
This study clearly indicates that Ang II significantly aggravated hypoperfusion and reperfusion microvascular damage via AT1 R and oxidative stress, whereas angiotensin 1-7 (Ang 1-7) prevented the damage in a model of rat pial microcirculation
Summary
The renin–angiotensin–system (RAS) can fine tune the amount of Ang II acting on microvascular networks. Renin facilitates the release of angiotensin I (Ang I) from angiotensinogen, a peptide released by the liver. Ang I can be processed by the classical angiotensin converting enzyme (ACE1), leading to the formation of Ang II, a molecule that causes arteriolar constriction and other microvascular effects through AT1 R [5]. Ang II can be processed by ACE2, a transmembrane metallopeptidase constituted. 805 amino acids, cloned by Tipnis and coworkers in 2000 [6].
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