Collagen XV Is Necessary for Modeling of the Extracellular Matrix and Its Deficiency Predisposes to Cardiomyopathy

• Published in: Circulation research Vol. 107; no. 10; pp. 1241 - 1252
• Main Authors: Rasi, Karolina, Piuhola, Jarkko, Czabanka, Marcus, Sormunen, Raija, Ilves, Mika, Leskinen, Hanna, Rysä, Jaana, Kerkelä, Risto, Janmey, Paul, Heljasvaara, Ritva, Peuhkurinen, Keijo, Vuolteenaho, Olli, Ruskoaho, Heikki, Vajkoczy, Peter, Pihlajaniemi, Taina, Eklund, Lauri
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 12.11.2010; Lippincott Williams & Wilkins
• Subjects: Age Factors; Aging; Angiotensin II; Animals; Arterial hypertension. Arterial hypotension; Atrial Natriuretic Factor - genetics; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiomyopathies - etiology; Cardiomyopathies - genetics; Cardiomyopathies - metabolism; Cardiomyopathies - physiopathology; Collagen - deficiency; Collagen - genetics; Collagen - metabolism; Coronary Circulation; Disease Models, Animal; Echocardiography; Elasticity; Enzyme Inhibitors; Extracellular Matrix - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling - methods; Gene Expression Regulation; Genotype; Heart; Heart Ventricles - metabolism; Heart Ventricles - physiopathology; Hemodynamics; Hypertension - chemically induced; Hypertension - complications; Hypertension - genetics; Hypertension - metabolism; Hypertension - physiopathology; Male; Medical sciences; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Microcirculation; Microscopy, Electron; Microscopy, Video; Myocarditis. Cardiomyopathies; Myocardium - metabolism; Myocardium - ultrastructure; Natriuretic Peptide, Brain - genetics; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Phenotype; Polymerase Chain Reaction; RNA, Messenger - metabolism; Telemetry; Ventricular Remodeling; Vertebrates: cardiovascular system; Hypertension; Cardiomyopathy; Glycoprotein; Cardiovascular disease; Myocardial disease; Modeling; Microcirculation; Vertebrata; Mammalia; Heart disease; Collagen; Extracellular matrix; Circulatory system
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.110.222133

RATIONALE:The extracellular matrix (ECM) is a major determinant of the structural integrity and functional properties of the myocardium in common pathological conditions, and changes in vasculature contribute to cardiac dysfunction. Collagen (Col) XV is preferentially expressed in the ECM of cardiac muscle and microvessels. OBJECTIVE:We aimed to characterize the ECM, cardiovascular function and responses to elevated cardiovascular load in mice lacking Col XV (Col15a1) to define its functional role in the vasculature and in age- and hypertension-associated myocardial remodeling. METHODS AND RESULTS:Cardiac structure and vasculature were analyzed by light and electron microscopy. Cardiac function, intraarterial blood pressure, microhemodynamics, and gene expression profiles were studied using echocardiography, telemetry, intravital microscopy, and PCR, respectively. Experimental hypertension was induced with angiotensin II or with a nitric oxide synthesis inhibitor. Under basal conditions, lack of Col XV resulted in increased permeability and impaired microvascular hemodynamics, distinct early-onset and age-dependent defects in heart structure and function, a poorly organized fibrillar collagen matrix with marked interstitial deposition of nonfibrillar protein aggregates, increased tissue stiffness, and irregularly organized cardiomyocytes. In response to experimental hypertension, Col15a1 gene expression was increased in the left ventricle of wild-type mice, and mRNA expression of natriuretic peptides (ANP and BNP) and ECM modeling were abnormal in Col15a1 mice. CONCLUSIONS:Col XV is necessary for ECM organization in the heart, and for the structure and functions of microvessels. Col XV deficiency leads to a complex cardiac phenotype and predisposes the subject to pathological responses under cardiac stress.