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

Robert P Mecham,Robyn A Roth,Michelle Lin,Carmen M Halabi,Beth A Kozel

doi:10.3389/fcvm.2021.782138

Abstract

There is ample evidence supporting a role for angiotensin II type 2 receptor (AT2R) 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 AT2R agonism in vitro suggesting that AT2R may have vasoconstrictor effects in elastin insufficiency. Given the potential promise for the use of AT2R agonists clinically, the goal of this study was to determine whether AT2R has vasoconstrictive effects in elastin insufficiency in vivo. To avoid off-target effects of agonists and antagonists, mice lacking AT2R (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 AT2R 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 AT2R in elastin insufficiency. Careful consideration and investigation are necessary to determine the patient population that might benefit from the use of AT2R agonists.

Highlights

Elastin (ELN), the main component of elastic fibers, is responsible for conduit arteries’ elastic recoil
Loss of angiotensin II type 2 receptor (AT2R) did not affect blood pressure at baseline [20] and Eln+/− mice exhibited systolic hypertension compared to wild-type (WT) littermates [6] (Figures 1A–C)
One of the characteristic features of elastin insufficiency is large artery stiffness assessed by pressure-diameter curves experimentally in Eln+/− mice and by pulse wave velocity in humans with Williams syndrome [4, 6]

Summary

Introduction

Elastin (ELN), the main component of elastic fibers, is responsible for conduit arteries’ elastic recoil. This recoil is necessary to dampen the pulsatile flow of ventricular ejection at the level of the ascending aorta and transform it into continuous flow at the level of arterioles or small resistance arteries. Decreased elasticity of large arteries with aging is attributed to fragmentation and thinning of these lamellae and results in increased pulse wave velocity leading to a greater augmentation of the central aortic systolic and pulse pressures [1, 2]. Genetic reduction of elastin through deletion of a single copy of the gene ELN (supravalvular aortic stenosis—SVAS, OMIM #185500) or deletion of ELN as part of a 25–27 coding gene microdeletion of chromosome 7 (Williams syndrome, OMIM #194050) leads to increased pulse wave velocity and hypertension [3,4,5].

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