Collagen XV is necessary for modeling of the extracellular matrix and its deficiency predisposes to cardiomyopathy.
BACKGROUND
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.


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.
Rasi
Karolina
K
Oulu Center for Cell-Matrix Research, Biocenter Oulu, University of Oulu, Finland.
Piuhola
Jarkko
J
Czabanka
Marcus
M
Sormunen
Raija
R
Ilves
Mika
M
Leskinen
Hanna
H
Rysä
Jaana
J
Kerkelä
Risto
R
Janmey
Paul
P
Heljasvaara
Ritva
R
Peuhkurinen
Keijo
K
Vuolteenaho
Olli
O
Ruskoaho
Heikki
H
Vajkoczy
Peter
P
Pihlajaniemi
Taina
T
Eklund
Lauri
L
D000367:Age Factors; D000375:Aging; D000804:Angiotensin II; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D009202:Cardiomyopathies / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003094:Collagen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003326:Coronary Circulation; D004195:Disease Models, Animal; D004452:Echocardiography; D004548:Elasticity; D004791:Enzyme Inhibitors; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D005838:Genotype; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics; D006973:Hypertension / Q000139:chemically induced / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation; D008854:Microscopy, Electron; D018715:Microscopy, Video; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D019331:NG-Nitroarginine Methyl Ester; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D013686:Telemetry; D020257:Ventricular Remodeling
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; C553732:collagen XV, mouse; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D003094:Collagen; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester