title: Mapping genetic determinants of coronary microvascular remodeling in the spontaneously hypertensive rat.
abstract: The mechanisms underlying coronary microvascular remodeling and dysfunction, which are critical determinants of abnormal myocardial blood flow regulation in human hypertension, are poorly understood. The spontaneously hypertensive rat (SHR) exhibits many features of human hypertensive cardiomyopathy. We demonstrate that remodeling of intramural coronary arterioles is apparent in the SHR already at 4 weeks of age, i.e. before the onset of systemic hypertension. To uncover possible genetic determinants of coronary microvascular remodeling, we carried out detailed histological and histomorphometric analysis of the heart and coronary vasculature in 30 weeks old SHR, age-matched Brown Norway (BN-Lx) parentals and BXH/HXB recombinant inbred (RI) strains. Using previously mapped expression quantitative trait loci (eQTLs), we carried out a genome-wide association analysis between genetic determinants of cardiac gene expression and histomorphometric traits. This identified 36 robustly mapped eQTLs in the heart which were associated with medial area of intramural coronary arterioles [false discovery rate (FDR) ~5%]. Transcripts, which were both under cis-acting genetic regulation and significantly correlated with medial area (FDR <5%), but not with blood pressure indices, were prioritized and four candidate genes were identified (Rtel1, Pla2g5, Dnaja4 and Rcn2) according to their expression levels and biological functions. Our results demonstrate that genetic factors play a role in the development of coronary microvascular remodeling and suggest blood pressure independent candidate genes for further functional experiments.
authors.affiliation: Department of Radiology, Oncology and Pathology, Sapienza University of Rome, Rome, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mancini
authors.forename: Enrico
authors.initials: E
authors.lastname: Petretto
authors.forename: Christina
authors.initials: C
authors.lastname: Kleinert
authors.forename: Angela
authors.initials: A
authors.lastname: Scavone
authors.forename: Tisham
authors.initials: T
authors.lastname: De
authors.forename: Stuart
authors.initials: S
authors.lastname: Cook
authors.forename: Jan
authors.initials: J
authors.lastname: Silhavy
authors.forename: Vaclav
authors.initials: V
authors.lastname: Zidek
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
authors.forename: Giulia
authors.initials: G
authors.lastname: d'Amati
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Camici
mesh_terms: D000818:Animals; D001794:Blood Pressure; D003331:Coronary Vessels / Q000473:pathology* / Q000503:physiopathology; D055106:Genome-Wide Association Study; D006973:Hypertension / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D055806:Microvessels / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D040641:Quantitative Trait Loci; D051381:Rats; D011914:Rats, Inbred BN; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY