Remodeling of the dermal extracellular matrix occurs during photoaging. Here, the effect of repetitive UVB irradiation on dermal hyaluronic acid (HA) was examined. C57/BL6 mice were chronically (182 days) irradiated with UVB, and consecutive skin biopsies were collected during the irradiation period and afterward (300 and 400 days of age). UVB caused marked loss of HA from the papillary dermis and down-regulation of HA synthase 1 (HAS1), HAS2, and HAS3 mRNA expression. In contrast, hyaluronidases (HYAL) 1, HYAL2, and HA receptor CD44 were unchanged. Furthermore, transforming growth factor ␤-1 (TGF-␤1) and TGF-␤1-receptor II expression were decreased in UVB-irradiated biopsies, and TGF-␤1 strongly induced HAS1 and HAS2 expression in cultured dermal fibroblasts. Therefore, TGF-␤1 might be one factor involved in UVB-induced down-regulation of HAS enzymes. In addition, total cell number and the percentage of proliferating fibroblasts in the papillary dermis of UVB-irradiated mice were decreased. Down-regulation of HAS2 by lentiviral overexpression of short hairpin RNA in vitro caused inhibition of HA synthesis, DNA synthesis, and migration of dermal fibroblasts. In conclusion, chronic UVB irradiation induces loss of HA from the dermis, thereby contributing to the quiescent phenotype of dermal fibroblasts. 1 Photoaging is the most common form of skin damage caused by chronic, repetitive sun exposure.2 The long-term exposure to solar UV irradiation induces damage to the dermal connective tissue and the extracellular matrix (ECM), which in turn leads to the aged appearance of photodamaged skin. Hallmark of this UV-induced ECM remodeling is the degradation of collagen and elastin through the UVB-induced activation of matrix metalloproteinases and decreased de novo synthesis of collagen. The mechanisms of UVB-induced matrix metalloproteinase activation 3 and inhibition of collagen synthesis have been studied in detail.2 In contrast the effect of UVB on hyaluronic acid (HA), another key component of the dermal ECM, is much less understood, and the underlying mechanisms are primarily unknown. HA is a linear polymer composed of repeating disaccharides (D-glucuronic acid-␤-1,3-N-acetylglucosamine-␤-1,4-) and assembled from the respective activated nucleotide sugars (UDPglucuronic acid, UDP-N-acetylglucosamine) at the inner plasma membrane by HA synthases (HAS). Three different HAS isoforms are known that reside in the plasma membrane and extrude the growing HA polymer into the extracellular space.4 HAS1 and HAS2 produce high molecular mass HA (2 to 4 ϫ 10 6 Da), whereas HAS3 synthesizes smaller HA (0.4 to 2.5 ϫ 10 5 Da). 5 The variation of the MW is the only modification of HA because O-or N-sulfations do not occur. HA is an agonist of CD44 and RHAMM (receptor of HA-mediated motility), which enables HA to initiate specific signaling events.6 This receptor signaling and the formation of pericellular HA coats supports proliferation and migration of a variety of cell types including skin fibroblasts. 7 In addition, antiapoptoti...

Background-After myocardial infarction (MI), extensive remodeling of extracellular matrix contributes to scar formation and preservation of hemodynamic function. On the other hand, adverse and excessive extracellular matrix remodeling leads to fibrosis and impaired function. The present study investigates the role of the small leucine-rich proteoglycan biglycan during cardiac extracellular matrix remodeling and cardiac hemodynamics after MI. Methods and Results-Experimental MI was induced in wild-type (WT) and bgn Ϫ/0 mice by permanent ligation of the left anterior descending coronary artery. Biglycan expression was strongly increased at 3, 7, and 14 days after MI in WT mice. bgn Ϫ/0 mice showed increased mortality rates after MI as a result of frequent left ventricular (LV) ruptures. Furthermore, tensile strength of the LV derived from bgn Ϫ/0 mice 21 days after MI was reduced as measured ex vivo. Collagen matrix organization was severely impaired in bgn Ϫ/0 mice, as shown by birefringence analysis of Sirius red staining and electron microscopy of collagen fibrils. At 21 days after MI, LV hemodynamic parameters were assessed by pressure-volume measurements in vivo to obtain LV end-diastolic pressure, end-diastolic volume, and end-systolic volume. bgn Ϫ/0 mice were characterized by aggravated LV dilation evidenced by increased LV end-diastolic volume (bgn

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Calcified atherosclerotic lesions are more prone to rupture during angioplasty than non-calcified lesions and are associated with an increased risk of thrombotic complications following angioplasty. This study investigates the possible role of extracellular matrix (ECM) calcification for platelet adhesion. Human cultured fibroblasts (CRL-1635) were subjected to beta-glycerophosphate (10 mM) for 10 to 16 days. Calcification was visualized by von Kossa staining and quantified by the O-cresolphthalein complexone method. Adhesion of calcein-labelled platelets was measured by fluorescence microscopy at static conditions and in a parallel-flow chamber at a shear rate of 1000 s(-1). beta-glycerophosphate treatment resulted in a marked calcification of the ECM. In parallel, a small, albeit significant increase in platelet adhesion under static conditions was observed. In contrast, at flow conditions, the area covered by thrombi was significantly lower when calcified ECM was used. The number of thrombi was not significantly different which is compatible with a smaller thrombus size. Taken together, it appears unlikely that calcification of atherosclerotic lesions contributes to thrombotic complications by an increased platelet adhesion.