Loss of Angiotensin II Type 2 Receptor Improves Blood Pressure in Elastin Insufficiency

There is ample evidence supporting a role for angiotensin II type 2 receptor (AT 2 R) in counterbalancing the effects of angiotensin II (ang II) through the angiotensin II type 1 receptor by promoting vasodilation and having anti-inflammatory effects. Elastin insufficiency in both humans and mice results in large artery stiffness and systolic hypertension. Unexpectedly, mesenteric arteries from elastin insufficient ( Eln +/− ) mice were shown to have significant vasoconstriction to AT 2 R agonism in vitro suggesting that AT 2 R may have vasoconstrictor effects in elastin insufficiency. Given the potential promise for the use of AT 2 R agonists clinically, the goal of this study was to determine whether AT 2 R has vasoconstrictive effects in elastin insufficiency in vivo . To avoid off-target effects of agonists and antagonists, mice lacking AT 2 R ( Agtr2 −/ Y ) were bred to Eln +/− mice and cardiovascular parameters were assessed in wild-type (WT), Agtr2 −/ Y , Eln +/− , and Agtr2 −/ Y ;Eln +/− littermates. As previously published, Agtr2 −/ Y mice were normotensive at baseline and had no large artery stiffness, while Eln +/− mice exhibited systolic hypertension and large artery stiffness. Loss of AT 2 R in Eln +/− mice did not affect large artery stiffness or arterial structure but resulted in significant reduction of both systolic and diastolic blood pressure. These data support a potential vasocontractile role for AT 2 R in elastin insufficiency. Careful consideration and investigation are necessary to determine the patient population that might benefit from the use of AT 2 R agonists.