Endothelial Mineralocorticoid Receptors Differentially Contribute to Coronary and Mesenteric Vascular Function Without Modulating Blood Pressure.
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.
From the Molecular Cardiology Research Institute, Tufts Medical Center, and Sackler School of Biomedical Graduate Studies, Tufts University School of Medicine, Boston, MA (K.B.M., M.A., I.Z.J.); Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., K.H., Y.Y., M.A.H.), and Department of Medical Pharmacology and Physiology, School of Medicine (K.H., M.A.H.), University of Missouri, Columbia; and INSERM, UMR 1138, Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (F.J.).
Katelee Barrett
KB
Mueller
From the Molecular Cardiology Research Institute, Tufts Medical Center, and Sackler School of Biomedical Graduate Studies, Tufts University School of Medicine, Boston, MA (K.B.M., M.A., I.Z.J.); Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., K.H., Y.Y., M.A.H.), and Department of Medical Pharmacology and Physiology, School of Medicine (K.H., M.A.H.), University of Missouri, Columbia; and INSERM, UMR 1138, Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (F.J.).
Shawn B
SB
Bender
From the Molecular Cardiology Research Institute, Tufts Medical Center, and Sackler School of Biomedical Graduate Studies, Tufts University School of Medicine, Boston, MA (K.B.M., M.A., I.Z.J.); Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., K.H., Y.Y., M.A.H.), and Department of Medical Pharmacology and Physiology, School of Medicine (K.H., M.A.H.), University of Missouri, Columbia; and INSERM, UMR 1138, Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (F.J.).
Kwangseok
K
Hong
From the Molecular Cardiology Research Institute, Tufts Medical Center, and Sackler School of Biomedical Graduate Studies, Tufts University School of Medicine, Boston, MA (K.B.M., M.A., I.Z.J.); Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., K.H., Y.Y., M.A.H.), and Department of Medical Pharmacology and Physiology, School of Medicine (K.H., M.A.H.), University of Missouri, Columbia; and INSERM, UMR 1138, Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (F.J.).
Yan
Y
Yang
From the Molecular Cardiology Research Institute, Tufts Medical Center, and Sackler School of Biomedical Graduate Studies, Tufts University School of Medicine, Boston, MA (K.B.M., M.A., I.Z.J.); Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., K.H., Y.Y., M.A.H.), and Department of Medical Pharmacology and Physiology, School of Medicine (K.H., M.A.H.), University of Missouri, Columbia; and INSERM, UMR 1138, Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (F.J.).
Mark
M
Aronovitz
From the Molecular Cardiology Research Institute, Tufts Medical Center, and Sackler School of Biomedical Graduate Studies, Tufts University School of Medicine, Boston, MA (K.B.M., M.A., I.Z.J.); Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., K.H., Y.Y., M.A.H.), and Department of Medical Pharmacology and Physiology, School of Medicine (K.H., M.A.H.), University of Missouri, Columbia; and INSERM, UMR 1138, Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (F.J.).
Frederic
F
Jaisser
From the Molecular Cardiology Research Institute, Tufts Medical Center, and Sackler School of Biomedical Graduate Studies, Tufts University School of Medicine, Boston, MA (K.B.M., M.A., I.Z.J.); Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., K.H., Y.Y., M.A.H.), and Department of Medical Pharmacology and Physiology, School of Medicine (K.H., M.A.H.), University of Missouri, Columbia; and INSERM, UMR 1138, Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (F.J.).
Michael A
MA
Hill
From the Molecular Cardiology Research Institute, Tufts Medical Center, and Sackler School of Biomedical Graduate Studies, Tufts University School of Medicine, Boston, MA (K.B.M., M.A., I.Z.J.); Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., K.H., Y.Y., M.A.H.), and Department of Medical Pharmacology and Physiology, School of Medicine (K.H., M.A.H.), University of Missouri, Columbia; and INSERM, UMR 1138, Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France (F.J.). ijaffe@tuftsmedicalcenter.org.
Iris Z
IZ
Jaffe
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006973:Hypertension / Q000503:physiopathology; D008297:Male; D008643:Mesentery / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018161:Receptors, Mineralocorticoid / Q000502:physiology*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology*; D012307:Risk Factors; D014655:Vascular Resistance / Q000502:physiology
D018161:Receptors, Mineralocorticoid; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester
blood pressure; endothelial cells; endothelin-1; hypertension; receptors, mineralocorticoid