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.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Lin, Roth, Kozel, Mecham and Halabi.)