Abstract
Collagen XV and XVIII are ubiquitous constituents of basement membranes. We aimed to study the physiological roles of these two components of the permeability barrier non-invasively in striated muscle in mice deficient in collagen XV or XVIII by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Structural information was obtained with transmission electron microscopy (TEM). MR data were analysed by two different analysis methods to quantify tissue perfusion and microcirculatory exchange parameters to rule out data analysis method-dependent results. Control mice (C57BL/6J Ola/Hsd strain) or mice lacking either collagen XV (Col15a1(-/-)) or XVIII (Col18a1(-/-)) were included in the study. MR images were acquired using a preclinical system using gadodiamide (Gd-DTPA-BMA, molecular weight 0.58 kDa) as a tracer. Exchange capacity (permeability (P)-surface area (S) product relative to blood flow (FB)) was increased in test mice compared to controls, but the contributions from P, S, and FB were different in these two phenotypes. FB was significantly increased in Col18a1(-/-), but slightly decreased in Col15a1(-/-). PS was significantly increased only in Col18a1(-/-) even though P was increased in both phenotypes suggesting S might also be reduced in Col15a1(-/-) mice. Immunohistochemistry and electron microscopy demonstrated alterations in capillary density and morphology in both knockout mouse strains in comparison to the control mice. Both collagen XV and XVIII are important for maintaining normal capillary permeability in the striated muscle. DCE-MRI and the perfusion analyses successfully determined microvascular haemodynamic parameters of genetically modified mice and gave results consistent with more invasive methods.
Highlights
In recent years, our understanding of the vascular basement membranes (BMs) has changed dramatically, from being mere structural components of tissues and barriers to infiltration to acting as an active modulator of blood vessel formation and function, including the properties of the microcirculatory exchange barrier (Sund et al 2004)
Representative MR images from animals in each group during the baseline, peak and clearance phase (Fig. 1C) demonstrate a uniform distribution throughout the deep masseter muscle within the same time frame, indicating that the results are not due to noise but to differences in microvascular function, i.e. that the depletion of collagen XV or collagen XVIII induced an altered circulatory phenotype compared to the control animals
Physiological data obtained with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) revealed altered microvascular function in Col15a1−/− and Col18a1−/− mice, indicating important roles of collagen XV and collagen XVIII in maintaining the vessel wall integrity
Summary
Our understanding of the vascular basement membranes (BMs) has changed dramatically, from being mere structural components of tissues and barriers to infiltration to acting as an active modulator of blood vessel formation and function, including the properties of the microcirculatory exchange barrier (Sund et al 2004). The vascular BM of normal blood vessels is a uniform, well-defined sheet-like extracellular matrix underlying the endothelial cell layer and separating the endothelial cells from the stroma. It serves as an anchor for the pericytes and provides the vessels additional structural support (Kalluri, 2003; Sund et al 2004). Collagen XVIII has structural properties typical of collagens, which includes several non-collagenous domains, and a proteoglycan with attached heparan sulphate side-chains. Collagen XV and XVIII form a distinct multiplexin group within the collagen superfamily (Myllyharju & Kivirikko, 2004) and their proteolytically cleaved C-terminal parts, named restin and endostatin are classified as endogenous angiogenesis inhibitors (Sund et al 2004; Iozzo, 2005)
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