Kidney Week

Abstract: TH-OR058

Angiotensin II Type 2 Receptor Contributes to Hypertension in Elastin Insufficiency

Session Information

• Hypertension: Off the Cuff - Treatment and Mechanisms
  November 02, 2017 | Location: Auditorium C, Morial Convention Center
  Abstract Time: 05:54 PM - 06:06 PM

Category: Hypertension

• 1103 Vascular Biology and Dysfunction

Author

• Halabi, Carmen M., Washington University School of Medicine, Saint Louis, Missouri, United States

Carmen M. Halabi, MD, PhD

Background

Hypertension and vascular stiffness are major consequences of elastin insufficiency, as seen in patients with Williams syndrome and animals models of elastin insufficiency. Altered reactivity of resistance vessels was recently proposed to contribute to hypertension in elastin insufficiency. Specifically, mesenteric arteries of elastin insufficient mice were shown to be hypercontractile to angiotensin II (AngII) ex vivo. Interestingly, this hypercontractile response to AngII was partially mediated by AngII type 2 receptors (AT2R) as blockade of AT2R by PD123319 abrogated the hypercontractile response to AngII. The purpose of this study was to determine whether AT2R contributes to the hypertension seen with elastin insufficiency in vivo.

Methods

Elastin haploinsufficient (Eln^het) mice were bred to AT2R knock-out (Agtr2^KO) mice. Arterial blood pressure measurement and large artery compliance studies were performed on three month-old male littermate progeny with the following genotypes (Agtr2^WT/Eln^WT; Agtr2^KO/Eln^WT; Agtr2^WT/Eln^het; and Agtr2^KO/Eln^het). Structural examination of ascending aorta and mesenteric arteries was done via Alexa-633 hydrazide staining and transmission electron microscopy, respectively.

Results

As expected, compared to wild type (WT) mice, loss of AT2R had no effect on blood pressure or large vessel compliance in the presence of WT elastin (Agtr2^KO/Eln^WT), while elastin insufficiency resulted in elevated systolic blood pressure, pulse pressure, and reduced large vessel compliance in the presence of AT2R (Agtr2^WT/Eln^het). Loss of AT2R in elastin insufficient mice (Agtr2^KO/Eln^het) resulted in significant reduction of systolic and diastolic blood pressures, but no change in pulse pressure or large artery compliance. There were no structural changes in either the ascending aortae or mesenteric arteries of Agtr2^KO/Eln^het compared to Agtr2^WT/Eln^het.

Conclusion

These results provide in vivo evidence for a role of AT2R in mediating elastin insufficiency-associated hypertension. Furthermore, these data suggest distinct mechanisms for the development of hypertension and vascular stiffness in elastin insufficiency, as loss of AT2R reduced blood pressure, but had no effect on large artery stiffness in this mouse model. Studies are underway to determine the effect of AT2R loss on resistance artery reactivity.

Funding

• Other NIH Support