title: The angiotensin receptor blocker losartan reduces coronary arteriole remodeling in type 2 diabetic mice.
abstract: Cardiovascular complications are a leading cause of morbidity and mortality in type 2 diabetes mellitus (T2DM) and are associated with alterations of blood vessel structure and function. Although endothelial dysfunction and aortic stiffness have been documented, little is known about the effects of T2DM on coronary microvascular structural remodeling. The renin-angiotensin-aldosterone system plays an important role in large artery stiffness and mesenteric vessel remodeling in hypertension and T2DM. The goal of this study was to determine whether the blockade of AT1R signaling dictates vascular smooth muscle growth that partially underlies coronary arteriole remodeling in T2DM. Control and db/db mice were given AT1R blocker losartan via drinking water for 4 weeks. Using pressure myography, we found that coronary arterioles from 16-week db/db mice undergo inward hypertrophic remodeling due to increased wall thickness and wall-to-lumen ratio with a decreased lumen diameter. This remodeling was accompanied by decreased elastic modulus (decreased stiffness). Losartan treatment decreased wall thickness, wall-to-lumen ratio, and coronary arteriole cell number in db/db mice. Losartan treatment did not affect incremental elastic modulus. However, losartan improved coronary flow reserve. Our data suggest that Ang II-AT1R signaling mediates, at least in part, coronary arteriole inward hypertrophic remodeling in T2DM without affecting vascular mechanics, further suggesting that targeting the coronary microvasculature in T2DM may help reduce cardiac ischemic events.
authors.affiliation: Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States; School of Biomedical Science, The Ohio State University College of Medicine, Columbus, OH, United States.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Husarek
authors.affiliation: Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States; Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, United States.
authors.forename: Paige S
authors.initials: PS
authors.lastname: Katz
authors.affiliation: Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, United States.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Trask
authors.affiliation: Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.
authors.forename: Maarten L
authors.initials: ML
authors.lastname: Galantowicz
authors.affiliation: Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Cismowski
authors.affiliation: Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, United States. Electronic address: Pamela.Lucchesi@nationwidechildrens.org.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Lucchesi
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000178:diet therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D051379:Mice; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010865:Pilot Projects; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects
chemical_list: D057911:Angiotensin Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D019808:Losartan
keywords: Angiotensin receptor blocker; Coronary arterioles; Type 2 diabetes mellitus; Vascular remodeling