Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Dec;70(6):1113-1121.
doi: 10.1161/HYPERTENSIONAHA.117.09598. Epub 2017 Oct 3.

Endothelial Mineralocorticoid Receptor Mediates Parenchymal Arteriole and Posterior Cerebral Artery Remodeling During Angiotensin II-Induced Hypertension

Janice M Diaz-Otero  1 , Courtney Fisher  2 , Kelsey Downs  2 , M Elizabeth Moss  2 , Iris Z Jaffe  2 , William F Jackson  2 , Anne M Dorrance  2
Affiliations

Endothelial Mineralocorticoid Receptor Mediates Parenchymal Arteriole and Posterior Cerebral Artery Remodeling During Angiotensin II-Induced Hypertension

Janice M Diaz-Otero et al. Hypertension. 2017 Dec.

Abstract

The brain is highly susceptible to injury caused by hypertension because the increased blood pressure causes artery remodeling that can limit cerebral perfusion. Mineralocorticoid receptor (MR) antagonism prevents hypertensive cerebral artery remodeling, but the vascular cell types involved have not been defined. In the periphery, the endothelial MR mediates hypertension-induced vascular injury, but cerebral and peripheral arteries are anatomically distinct; thus, these findings cannot be extrapolated to the brain. The parenchymal arterioles determine cerebrovascular resistance. Determining the effects of hypertension and MR signaling on these arterioles could lead to a better understanding of cerebral small vessel disease. We hypothesized that endothelial MR signaling mediates inward cerebral artery remodeling and reduced cerebral perfusion during angiotensin II (AngII) hypertension. The biomechanics of the parenchymal arterioles and posterior cerebral arteries were studied in male C57Bl/6 and endothelial cell-specific MR knockout mice and their appropriate controls using pressure myography. AngII increased plasma aldosterone and decreased cerebral perfusion in C57Bl/6 and MR-intact littermates. Endothelial cell MR deletion improved cerebral perfusion in AngII-treated mice. AngII hypertension resulted in inward hypotrophic remodeling; this was prevented by MR antagonism and endothelial MR deletion. Our studies suggest that endothelial cell MR mediates hypertensive remodeling in the cerebral microcirculation and large pial arteries. AngII-induced inward remodeling of cerebral arteries and arterioles was associated with a reduction in cerebral perfusion that could worsen the outcome of stroke or contribute to vascular dementia.

Keywords: endothelium; hypertension; mice; microcirculation; stroke.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Endothelial MR deletion prevents a reduction in cerebral perfusion with AngII-hypertension
Cerebral perfusion was measured prior to euthanasia in anesthetized mice using scanning laser Doppler. Representative images of the scanning laser Doppler are shown (A, B). In Figures C and D, data are presented as mean ± SEM. (C) Mean cerebral perfusion was reduced in AngII treated mice compared to Sham. Cerebral perfusion was improved in the AngII+EPL treated C57Bl/6 mice. (D) EC-MR deletion did not change baseline perfusion compared to MR-intact. AngII-hypertension decreased cerebral perfusion in MR-intact mice. EC-MR deletion in the ECMRKO+AngII significantly increased perfusion compared to the MR-intact+AngII mice. *p<0.05; vs. Sham, MR-intact or ECMRKO. #p<0.05 AngII vs. AngII+EPL or MR-intact+AngII vs. ECMRKO+AngII. Legend: Eplerenone (EPL); Angiotensin II (AngII); Mineralocorticoid receptor-intact mice (MR-intact); Endothelial cell MR knockout (ECMRKO).
Figure 2
Figure 2. AngII-hypertension increases plasma aldosterone in C57bl/6 and EMCRKO mice
Plasma aldosterone and corticosterone were measured after 4 weeks of AngII or vehicle treatment. (A) EPL treatment increased plasma aldosterone levels when compared to Sham C57bl/6 mice. AngII-hypertension also increased plasma aldosterone, AngII+EPL treatment did not further increase aldosterone levels in C57Bl/6 mice. (B) EC-MR deletion did not alter plasma aldosterone levels when compared to MR-intact littermates in the absence of hypertension. AngII infusion significantly increased aldosterone levels in MR-intact and ECMRKO mice. (C-D) AngII-induced hypertension did not change plasma corticosterone levels. Data are presented as mean ± SEM. *p<0.05 vs Sham or MR-intact and ECMRKO. Legend: Eplerenone (EPL); Angiotensin II (AngII); Mineralocorticoid receptor-intact mice (MR-intact); Endothelial cell MR knockout (ECMRKO).
Figure 3
Figure 3. MR antagonism prevents PA inward hypotrophic remodeling with AngII-hypertension
The biomechanical properties were assessed in isolated PAs using pressure myography. AngII infusion resulted in a reduced (A) outer diameter, (B) lumen diameter, and (C) wall-cross sectional area. (D) Wall-to-lumen ratio was increased in the AngII treated mice. EPL treatment prevented these changes. (E) Wall stress was significantly reduced. However, (F) artery wall stiffness was not changed. Data are presented as mean ± SEM. *p<0.05 vs Sham or AngII+EPL. Legend: Eplerenone (EPL); Angiotensin II (AngII).
Figure 4
Figure 4. MR antagonism prevents inward remodeling of the PCA during AngII-hypertension
Structure was assessed in isolated PCAs using pressure myography. The (A) outer and (B) lumen diameter were reduced in AngII treated mice. (C)Wall cross sectional area was reduced at 120mmHg. (D) Wall-to-lumen ratio was not changed. EPL treatment prevented the inward remodeling of the posterior cerebral artery. (E) Wall stress and (F) wall stiffness remained unchanged. Data are presented as mean ± SEM. *p<0.05 vs Sham or Ang+EPL. Legend: Eplerenone (EPL); Angiotensin II (AngII).
Figure 5
Figure 5. Endothelial MR signaling mediates PA remodeling during AngII-hypertension
AngII-hypertension significantly reduced the (A) outer diameter, (B) lumen diameter, and (C) wall area in MR-intact+AngII compared to MR-intact mice. (D) Wall-to-lumen ratio was increased in MR-intact mice. (E) Wall stress was also changed, but (F) wall stiffness was not significantly changed. Endothelial MR deletion prevented the inward hypotrophic remodeling but it did not increase the wall stress. Data are presented as mean ± SEM. *p<0.05 vs MR-intact or ECMRKO+AngII. Legend: Angiotensin II (AngII); Mineralocorticoid receptor-intact mice (MR-intact); Endothelial cell MR knockout (ECMRKO).
Figure 6
Figure 6. Endothelial MR deletion prevents posterior cerebral artery remodeling during AngII-hypertension
Structure was assessed in isolated arteries using pressure myography. AngII infusion resulted in inward remodeling evidenced by the reduced (A) outer, and (B) lumen diameter in the MR-intact+AngII compared to MR-intact mice. EC-MR deletion prevented the inward remodeling in the ECMRKO+AngII mice. (C) Wall area was not significantly changed in the MR-intact+AngII compared to MR-intact, but it was significantly increased in the ECMRKO+AngII compared to MR-intact+AngII mice. (D) Wall-to-lumen ratio did not change. (E) Wall stress was reduced in the MR-intact+AngII and ECMRKO+AngII compared to MR-intact. (F)Artery wall stiffness was not changed. Data are presented as mean ± SEM. *p<0.05 vs MR-intact or ECMRKO+AngII; #p<0.05 MR-intact+AngII vs ECMRKO+AngII. Legend: Angiotensin II (AngII); Mineralocorticoid receptor-intact mice (MR-intact); Endothelial cell MR knockout (ECMRKO).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Sierra C. Cerebral small vessel disease, cognitive impairment and vascular dementia. Panminerva Med. 2012;54(3):179–88. - PubMed
    1. Dichgans M, Zietemann V. Prevention of vascular cognitive impairment. Stroke. 2012;43(11):3137–46. doi: 10.1161/STROKEAHA.112.651778. - DOI - PubMed
    1. Pires PW, Dams Ramos CM, Matin N, Dorrance AM. The effects of hypertension on the cerebral circulation. Am J Physiol Heart Circ Physiol. 2013;304(12):H1598–614. doi: 10.1152/ajpheart.00490.2012. - DOI - PMC - PubMed
    1. Rigsby CS, Pollock DM, Dorrance AM. Spironolactone improves structure and increases tone in the cerebral vasculature of male spontaneously hypertensive stroke-prone rats. Microvasc Res. 2007;73(3):198–205. doi: 10.1016/j.mvr.2006.12.001. - DOI - PMC - PubMed
    1. Pires PW, Jackson WF, Dorrance AM. Regulation of myogenic tone and structure of parenchymal arterioles by hypertension and the mineralocorticoid receptor. Am J Physiol Heart Circ Physiol. 2015;309(1):H127–36. doi: 10.1152/ajpheart.00168.2015. - DOI - PMC - PubMed

Publication types

Substances