Endothelial Mineralocorticoid Receptors Differentially Contribute to Coronary and Mesenteric Vascular Function Without Modulating Blood Pressure
Katelee Barrett Mueller, Shawn B Bender, Kwangseok Hong, Yan Yang, Mark Aronovitz, Frederic Jaisser, Michael A Hill, Iris Z Jaffe, Katelee Barrett Mueller, Shawn B Bender, Kwangseok Hong, Yan Yang, Mark Aronovitz, Frederic Jaisser, Michael A Hill, Iris Z Jaffe
Abstract
Arteriolar vasoreactivity tightly regulates tissue-specific blood flow and contributes to systemic blood pressure (BP) but becomes dysfunctional in the setting of cardiovascular disease. The mineralocorticoid receptor (MR) is known to regulate BP via the kidney and by vasoconstriction in smooth muscle cells. Although endothelial cells (EC) express MR, the contribution of EC-MR to BP and resistance vessel function remains unclear. To address this, we created a mouse with MR specifically deleted from EC (EC-MR knockout [EC-MR-KO]) but with intact leukocyte MR expression and normal renal MR function. Telemetric BP studies reveal no difference between male EC-MR-KO mice and MR-intact littermates in systolic, diastolic, circadian, or salt-sensitive BP or in the hypertensive responses to aldosterone±salt or angiotensin II±l-nitroarginine methyl ester. Vessel myography demonstrated normal vasorelaxation in mesenteric and coronary arterioles from EC-MR-KO mice. After exposure to angiotensin II-induced hypertension, impaired endothelial-dependent relaxation was prevented in EC-MR-KO mice in mesenteric vessels but not in coronary vessels. Mesenteric vessels from angiotensin II-exposed EC-MR-KO mice showed increased maximum responsiveness to acetylcholine when compared with MR-intact vessels, a difference that is lost with indomethacin+l-nitroarginine methyl ester pretreatment. These data support that EC-MR plays a role in regulating endothelial function in hypertension. Although there was no effect of EC-MR deletion on mesenteric vasoconstriction, coronary arterioles from EC-MR-KO mice showed decreased constriction to endothelin-1 and thromboxane agonist at baseline and also after exposure to hypertension. These data support that EC-MR participates in regulation of vasomotor function in a vascular bed-specific manner that is also modulated by risk factors, such as hypertension.
Keywords: blood pressure; endothelial cells; endothelin-1; hypertension; receptors, mineralocorticoid.
Conflict of interest statement
Disclosures: The authors declare no conflicts of interest.
© 2015 American Heart Association, Inc.
Figures
![Figure 1. A mouse model with MR…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4600033/bin/nihms716622f1.jpg)
Figure 2. EC-MR does not contribute to…
Figure 2. EC-MR does not contribute to basal, salt sensitive, aldosterone/salt-enhanced, or angiotensin-enhanced BP
(A)…
Figure 3. EC-MR does not contribute to…
Figure 3. EC-MR does not contribute to mesenteric or coronary vasodilation
Sodium nitroprusside (SNP) and…
Figure 4. EC-MR deletion modulates mesenteric endothelial-dependent…
Figure 4. EC-MR deletion modulates mesenteric endothelial-dependent relaxation after exposure to AngII-induced hypertension
Mesenteric arterioles…
Figure 5. EC-MR differentially regulates vasoconstriction depending…
Figure 5. EC-MR differentially regulates vasoconstriction depending on the vascular bed and the contractile agonist
Figure 6. Decreased coronary vasoconstriction to endothelin-1…
Figure 6. Decreased coronary vasoconstriction to endothelin-1 and U46619 after hypertension and decreased EC endothelin-B…
- Endothelial cell mineralocorticoid receptors regulate deoxycorticosterone/salt-mediated cardiac remodeling and vascular reactivity but not blood pressure.Rickard AJ, Morgan J, Chrissobolis S, Miller AA, Sobey CG, Young MJ. Rickard AJ, et al. Hypertension. 2014 May;63(5):1033-40. doi: 10.1161/HYPERTENSIONAHA.113.01803. Epub 2014 Feb 24. Hypertension. 2014. PMID: 24566081
- The endothelial mineralocorticoid receptor regulates vasoconstrictor tone and blood pressure.Nguyen Dinh Cat A, Griol-Charhbili V, Loufrani L, Labat C, Benjamin L, Farman N, Lacolley P, Henrion D, Jaisser F. Nguyen Dinh Cat A, et al. FASEB J. 2010 Jul;24(7):2454-63. doi: 10.1096/fj.09-147926. Epub 2010 Mar 18. FASEB J. 2010. PMID: 20299606
- Endothelial mineralocorticoid receptor ablation does not alter blood pressure, kidney function or renal vessel contractility.Laursen SB, Finsen S, Marcussen N, Quaggin SE, Hansen PBL, Dimke H. Laursen SB, et al. PLoS One. 2018 Feb 21;13(2):e0193032. doi: 10.1371/journal.pone.0193032. eCollection 2018. PLoS One. 2018. PMID: 29466427 Free PMC article.
- Direct contribution of vascular mineralocorticoid receptors to blood pressure regulation.Barrett KV, McCurley AT, Jaffe IZ. Barrett KV, et al. Clin Exp Pharmacol Physiol. 2013 Dec;40(12):902-9. doi: 10.1111/1440-1681.12125. Clin Exp Pharmacol Physiol. 2013. PMID: 23710823 Free PMC article. Review.
- Smooth muscle cell mineralocorticoid receptors: role in vascular function and contribution to cardiovascular disease.McCurley A, McGraw A, Pruthi D, Jaffe IZ. McCurley A, et al. Pflugers Arch. 2013 Dec;465(12):1661-70. doi: 10.1007/s00424-013-1282-4. Epub 2013 May 1. Pflugers Arch. 2013. PMID: 23636772 Free PMC article. Review.
- Cardiovascular Disease in Obstructive Sleep Apnea: Putative Contributions of Mineralocorticoid Receptors.Badran M, Bender SB, Gozal D. Badran M, et al. Int J Mol Sci. 2023 Jan 23;24(3):2245. doi: 10.3390/ijms24032245. Int J Mol Sci. 2023. PMID: 36768567 Free PMC article. Review.
- Endothelial cell-specific mineralocorticoid receptor activation promotes diastolic dysfunction in diet-induced obese male mice.Aroor A, DeMarco VG, Whaley-Connell AT, Jia G, Yang Y, Sharma N, Naz H, Hans C, Hayden MR, Hill MA, Sowers JR, Manrique-Acevedo C, Lastra G. Aroor A, et al. Am J Physiol Regul Integr Comp Physiol. 2023 Jan 1;324(1):R90-R101. doi: 10.1152/ajpregu.00274.2021. Epub 2022 Nov 28. Am J Physiol Regul Integr Comp Physiol. 2023. PMID: 36440901
- Emerging vascular cell-specific roles for mineralocorticoid receptor: implications for understanding sex differences in cardiovascular disease.Wolter NL, Jaffe IZ. Wolter NL, et al. Am J Physiol Cell Physiol. 2023 Jan 1;324(1):C193-C204. doi: 10.1152/ajpcell.00372.2022. Epub 2022 Nov 28. Am J Physiol Cell Physiol. 2023. PMID: 36440858 Review.
- Mineralocorticoid Receptor Activation in Vascular Insulin Resistance and Dysfunction.Igbekele AE, Jia G, Hill MA, Sowers JR, Jia G. Igbekele AE, et al. Int J Mol Sci. 2022 Aug 11;23(16):8954. doi: 10.3390/ijms23168954. Int J Mol Sci. 2022. PMID: 36012219 Free PMC article. Review.
- Primary Aldosteronism: State-of-the-Art Review.Vaidya A, Hundemer GL, Nanba K, Parksook WW, Brown JM. Vaidya A, et al. Am J Hypertens. 2022 Dec 8;35(12):967-988. doi: 10.1093/ajh/hpac079. Am J Hypertens. 2022. PMID: 35767459
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Acetylcholine / pharmacology
- Animals
- Blood Pressure / physiology*
- Coronary Vessels / drug effects
- Coronary Vessels / physiology*
- Disease Models, Animal
- Endothelium, Vascular / drug effects
- Endothelium, Vascular / physiology*
- Hypertension / physiopathology
- Male
- Mesentery / drug effects
- Mesentery / physiology*
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- NG-Nitroarginine Methyl Ester / pharmacology
- Receptors, Mineralocorticoid / physiology*
- Regional Blood Flow / drug effects
- Regional Blood Flow / physiology*
- Risk Factors
- Vascular Resistance / physiology
- Receptors, Mineralocorticoid
- Acetylcholine
- NG-Nitroarginine Methyl Ester
- Full Text Sources
- Medical
- Molecular Biology Databases
- Research Materials
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 2. EC-MR does not contribute to…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4600033/bin/nihms716622f2.jpg)
![Figure 3. EC-MR does not contribute to…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4600033/bin/nihms716622f3.jpg)
![Figure 4. EC-MR deletion modulates mesenteric endothelial-dependent…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4600033/bin/nihms716622f4.jpg)
Figure 5. EC-MR differentially regulates vasoconstriction depending…
Figure 5. EC-MR differentially regulates vasoconstriction depending on the vascular bed and the contractile agonist
Figure 6. Decreased coronary vasoconstriction to endothelin-1…
Figure 6. Decreased coronary vasoconstriction to endothelin-1 and U46619 after hypertension and decreased EC endothelin-B…
- Endothelial cell mineralocorticoid receptors regulate deoxycorticosterone/salt-mediated cardiac remodeling and vascular reactivity but not blood pressure.Rickard AJ, Morgan J, Chrissobolis S, Miller AA, Sobey CG, Young MJ. Rickard AJ, et al. Hypertension. 2014 May;63(5):1033-40. doi: 10.1161/HYPERTENSIONAHA.113.01803. Epub 2014 Feb 24. Hypertension. 2014. PMID: 24566081
- The endothelial mineralocorticoid receptor regulates vasoconstrictor tone and blood pressure.Nguyen Dinh Cat A, Griol-Charhbili V, Loufrani L, Labat C, Benjamin L, Farman N, Lacolley P, Henrion D, Jaisser F. Nguyen Dinh Cat A, et al. FASEB J. 2010 Jul;24(7):2454-63. doi: 10.1096/fj.09-147926. Epub 2010 Mar 18. FASEB J. 2010. PMID: 20299606
- Endothelial mineralocorticoid receptor ablation does not alter blood pressure, kidney function or renal vessel contractility.Laursen SB, Finsen S, Marcussen N, Quaggin SE, Hansen PBL, Dimke H. Laursen SB, et al. PLoS One. 2018 Feb 21;13(2):e0193032. doi: 10.1371/journal.pone.0193032. eCollection 2018. PLoS One. 2018. PMID: 29466427 Free PMC article.
- Direct contribution of vascular mineralocorticoid receptors to blood pressure regulation.Barrett KV, McCurley AT, Jaffe IZ. Barrett KV, et al. Clin Exp Pharmacol Physiol. 2013 Dec;40(12):902-9. doi: 10.1111/1440-1681.12125. Clin Exp Pharmacol Physiol. 2013. PMID: 23710823 Free PMC article. Review.
- Smooth muscle cell mineralocorticoid receptors: role in vascular function and contribution to cardiovascular disease.McCurley A, McGraw A, Pruthi D, Jaffe IZ. McCurley A, et al. Pflugers Arch. 2013 Dec;465(12):1661-70. doi: 10.1007/s00424-013-1282-4. Epub 2013 May 1. Pflugers Arch. 2013. PMID: 23636772 Free PMC article. Review.
- Cardiovascular Disease in Obstructive Sleep Apnea: Putative Contributions of Mineralocorticoid Receptors.Badran M, Bender SB, Gozal D. Badran M, et al. Int J Mol Sci. 2023 Jan 23;24(3):2245. doi: 10.3390/ijms24032245. Int J Mol Sci. 2023. PMID: 36768567 Free PMC article. Review.
- Endothelial cell-specific mineralocorticoid receptor activation promotes diastolic dysfunction in diet-induced obese male mice.Aroor A, DeMarco VG, Whaley-Connell AT, Jia G, Yang Y, Sharma N, Naz H, Hans C, Hayden MR, Hill MA, Sowers JR, Manrique-Acevedo C, Lastra G. Aroor A, et al. Am J Physiol Regul Integr Comp Physiol. 2023 Jan 1;324(1):R90-R101. doi: 10.1152/ajpregu.00274.2021. Epub 2022 Nov 28. Am J Physiol Regul Integr Comp Physiol. 2023. PMID: 36440901
- Emerging vascular cell-specific roles for mineralocorticoid receptor: implications for understanding sex differences in cardiovascular disease.Wolter NL, Jaffe IZ. Wolter NL, et al. Am J Physiol Cell Physiol. 2023 Jan 1;324(1):C193-C204. doi: 10.1152/ajpcell.00372.2022. Epub 2022 Nov 28. Am J Physiol Cell Physiol. 2023. PMID: 36440858 Review.
- Mineralocorticoid Receptor Activation in Vascular Insulin Resistance and Dysfunction.Igbekele AE, Jia G, Hill MA, Sowers JR, Jia G. Igbekele AE, et al. Int J Mol Sci. 2022 Aug 11;23(16):8954. doi: 10.3390/ijms23168954. Int J Mol Sci. 2022. PMID: 36012219 Free PMC article. Review.
- Primary Aldosteronism: State-of-the-Art Review.Vaidya A, Hundemer GL, Nanba K, Parksook WW, Brown JM. Vaidya A, et al. Am J Hypertens. 2022 Dec 8;35(12):967-988. doi: 10.1093/ajh/hpac079. Am J Hypertens. 2022. PMID: 35767459
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Acetylcholine / pharmacology
- Animals
- Blood Pressure / physiology*
- Coronary Vessels / drug effects
- Coronary Vessels / physiology*
- Disease Models, Animal
- Endothelium, Vascular / drug effects
- Endothelium, Vascular / physiology*
- Hypertension / physiopathology
- Male
- Mesentery / drug effects
- Mesentery / physiology*
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- NG-Nitroarginine Methyl Ester / pharmacology
- Receptors, Mineralocorticoid / physiology*
- Regional Blood Flow / drug effects
- Regional Blood Flow / physiology*
- Risk Factors
- Vascular Resistance / physiology
- Receptors, Mineralocorticoid
- Acetylcholine
- NG-Nitroarginine Methyl Ester
- Full Text Sources
- Medical
- Molecular Biology Databases
- Research Materials
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 5. EC-MR differentially regulates vasoconstriction depending…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4600033/bin/nihms716622f5.jpg)
Figure 6. Decreased coronary vasoconstriction to endothelin-1…
Figure 6. Decreased coronary vasoconstriction to endothelin-1 and U46619 after hypertension and decreased EC endothelin-B…
- Endothelial cell mineralocorticoid receptors regulate deoxycorticosterone/salt-mediated cardiac remodeling and vascular reactivity but not blood pressure.Rickard AJ, Morgan J, Chrissobolis S, Miller AA, Sobey CG, Young MJ. Rickard AJ, et al. Hypertension. 2014 May;63(5):1033-40. doi: 10.1161/HYPERTENSIONAHA.113.01803. Epub 2014 Feb 24. Hypertension. 2014. PMID: 24566081
- The endothelial mineralocorticoid receptor regulates vasoconstrictor tone and blood pressure.Nguyen Dinh Cat A, Griol-Charhbili V, Loufrani L, Labat C, Benjamin L, Farman N, Lacolley P, Henrion D, Jaisser F. Nguyen Dinh Cat A, et al. FASEB J. 2010 Jul;24(7):2454-63. doi: 10.1096/fj.09-147926. Epub 2010 Mar 18. FASEB J. 2010. PMID: 20299606
- Endothelial mineralocorticoid receptor ablation does not alter blood pressure, kidney function or renal vessel contractility.Laursen SB, Finsen S, Marcussen N, Quaggin SE, Hansen PBL, Dimke H. Laursen SB, et al. PLoS One. 2018 Feb 21;13(2):e0193032. doi: 10.1371/journal.pone.0193032. eCollection 2018. PLoS One. 2018. PMID: 29466427 Free PMC article.
- Direct contribution of vascular mineralocorticoid receptors to blood pressure regulation.Barrett KV, McCurley AT, Jaffe IZ. Barrett KV, et al. Clin Exp Pharmacol Physiol. 2013 Dec;40(12):902-9. doi: 10.1111/1440-1681.12125. Clin Exp Pharmacol Physiol. 2013. PMID: 23710823 Free PMC article. Review.
- Smooth muscle cell mineralocorticoid receptors: role in vascular function and contribution to cardiovascular disease.McCurley A, McGraw A, Pruthi D, Jaffe IZ. McCurley A, et al. Pflugers Arch. 2013 Dec;465(12):1661-70. doi: 10.1007/s00424-013-1282-4. Epub 2013 May 1. Pflugers Arch. 2013. PMID: 23636772 Free PMC article. Review.
- Cardiovascular Disease in Obstructive Sleep Apnea: Putative Contributions of Mineralocorticoid Receptors.Badran M, Bender SB, Gozal D. Badran M, et al. Int J Mol Sci. 2023 Jan 23;24(3):2245. doi: 10.3390/ijms24032245. Int J Mol Sci. 2023. PMID: 36768567 Free PMC article. Review.
- Endothelial cell-specific mineralocorticoid receptor activation promotes diastolic dysfunction in diet-induced obese male mice.Aroor A, DeMarco VG, Whaley-Connell AT, Jia G, Yang Y, Sharma N, Naz H, Hans C, Hayden MR, Hill MA, Sowers JR, Manrique-Acevedo C, Lastra G. Aroor A, et al. Am J Physiol Regul Integr Comp Physiol. 2023 Jan 1;324(1):R90-R101. doi: 10.1152/ajpregu.00274.2021. Epub 2022 Nov 28. Am J Physiol Regul Integr Comp Physiol. 2023. PMID: 36440901
- Emerging vascular cell-specific roles for mineralocorticoid receptor: implications for understanding sex differences in cardiovascular disease.Wolter NL, Jaffe IZ. Wolter NL, et al. Am J Physiol Cell Physiol. 2023 Jan 1;324(1):C193-C204. doi: 10.1152/ajpcell.00372.2022. Epub 2022 Nov 28. Am J Physiol Cell Physiol. 2023. PMID: 36440858 Review.
- Mineralocorticoid Receptor Activation in Vascular Insulin Resistance and Dysfunction.Igbekele AE, Jia G, Hill MA, Sowers JR, Jia G. Igbekele AE, et al. Int J Mol Sci. 2022 Aug 11;23(16):8954. doi: 10.3390/ijms23168954. Int J Mol Sci. 2022. PMID: 36012219 Free PMC article. Review.
- Primary Aldosteronism: State-of-the-Art Review.Vaidya A, Hundemer GL, Nanba K, Parksook WW, Brown JM. Vaidya A, et al. Am J Hypertens. 2022 Dec 8;35(12):967-988. doi: 10.1093/ajh/hpac079. Am J Hypertens. 2022. PMID: 35767459
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Acetylcholine / pharmacology
- Animals
- Blood Pressure / physiology*
- Coronary Vessels / drug effects
- Coronary Vessels / physiology*
- Disease Models, Animal
- Endothelium, Vascular / drug effects
- Endothelium, Vascular / physiology*
- Hypertension / physiopathology
- Male
- Mesentery / drug effects
- Mesentery / physiology*
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- NG-Nitroarginine Methyl Ester / pharmacology
- Receptors, Mineralocorticoid / physiology*
- Regional Blood Flow / drug effects
- Regional Blood Flow / physiology*
- Risk Factors
- Vascular Resistance / physiology
- Receptors, Mineralocorticoid
- Acetylcholine
- NG-Nitroarginine Methyl Ester
- Full Text Sources
- Medical
- Molecular Biology Databases
- Research Materials
![Figure 6. Decreased coronary vasoconstriction to endothelin-1…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4600033/bin/nihms716622f6.jpg)
Source: PubMed