SummaryMerosin-deficient congenital muscular dystrophy 1A (MDC1A) is a devastating neuromuscular disease that results in children being confined to a wheelchair, requiring ventilator assistance to breathe and premature death. MDC1A is caused by mutations in the LAMA2 gene, which results in the partial or complete loss of laminin-211 and laminin-221, the major laminin isoforms found in the basal lamina of skeletal muscle. MDC1A patients exhibit reduced 71 integrin; however, it is unclear how the secondary loss of 71 integrin contributes to MDC1A disease progression. To investigate whether restoring 7 integrin expression can alleviate the myopathic phenotype observed in MDC1A, we produced transgenic mice that overexpressed the 7 integrin in the skeletal muscle of the dy W-/-mouse model of MDC1A. Enhanced expression of the 7 integrin restored sarcolemmal localization of the 71 integrin to laminin-2-deficient myofibers, changed the composition of the muscle extracellular matrix, reduced muscle pathology, maintained muscle strength and function and improved the life expectancy of dy W-/-mice. Taken together, these results indicate that enhanced expression of 7 integrin prevents muscle disease progression through augmentation and/or stabilization of the existing extracellular matrix in laminin-2-deficient mice, and strategies that increase 7 integrin in muscle might provide an innovative approach for the treatment of MDC1A.

Abstract-VascularV ascular smooth muscle cell (VSMC) proliferation and migration are major underlying factors in the development and progression of various forms of cardiovascular disease, including atherosclerosis, postangioplasty restenosis, transplant arteriopathy, and pulmonary hypertension. 1 Vascular remodeling during disease or injury involves altered expression of extracellular matrix proteins and cell surface integrins. 2-4 After arterial injury, laminin expression is reduced and fibronectin accumulates around VSMCs. 5,6 These changes coincide with a phenotypic switch in which contractile VSMCs adopt a proliferative phenotype, possibly as part of a developmental program associated with wound repair. 2,4 Integrins are transmembrane mechanosensors that relay signals from the extracellular matrix to the cell cytoskeleton and/or cell signaling pathways to modulate cell shape, adhesion, differentiation, proliferation, and contraction. 7 Various integrins modulate cell proliferation, usually by crosstalk with proliferative cell signaling pathways or in cooperation with growth factor receptors. 8 The ␣7␤1 integrin is a major laminin-binding receptor in VSMCs, and expression of this integrin increases after differentiation. 9 Previous studies using blocking antibodies and peptides have demonstrated that the ␣7␤1 integrin mediates adhesion of VSMCs to laminin in vitro. 9,10 Expression of this integrin has also been shown to be modulated by chemically induced injury and platelet-derived growth factor in cultured rat VSMCs. 10,11 We have previously demonstrated that embryonic loss of the ␣7 integrin results in vascular defects and partial embryonic lethality, whereas in adult mice, loss of the ␣7 integrin results in VSMC hyperplasia. 12 Loss of the ␣7␤1 integrin in VSMCs leads to altered expression of other integrin chains, which may contribute to the vascular phenotype observed in ␣7 integrin-null mice. 12 These observations have led to the hypothesis that the ␣7␤1 integrin promotes the contractile phenotype of VSMCs, but the mechanism of this regulation is unclear.Activation of the extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase signaling Original

Ohama T, Hori M, Momotani E, Elorza M, Gerthoffer WT, Ozaki H. IL-1␤ inhibits intestinal smooth muscle proliferation in an organ culture system: involvement of COX-2 and iNOS induction in muscularis resident macrophages. Am J Physiol Gastrointest Liver Physiol 292: G1315-G1322, 2007. First published January 18, 2007 doi:10.1152/ajpgi.00487.2006.-Intestinal inflammation causes hyperplasia of smooth muscle that leads to thickening of the smooth muscle layer, resulting in dysmotility. IL-1␤ is a proinflammatory cytokine that plays a central role in intestinal inflammation. In this study, to evaluate the effect of IL-1␤ on proliferation of ileal smooth muscle cells in vivo, we utilized an organ culture system. When rat ileal smooth muscle tissue was cultured under serum-free conditions for 3 days, most smooth muscle cells maintained their arrangement and kept their contractile phenotype. When 10% FBS was added, an increased number of smooth muscle cells per unit area was observed. Moreover, immunohistochemical staining for PCNA demonstrated that FBS induced proliferation of smooth muscle cells. IL-1␤ inhibited the proliferative effect of FBS. Furthermore, IL-1␤ upregulated inducible nitric oxide (NO) synthase and cyclooxygenase-2 mRNA and protein and thus stimulated NO and PGE 2 productions. Moreover, exogenously applied NO and PGE 2 inhibited the increase of bromodeoxyuridine-positive cells stimulated with FBS. Immunostaining revealed that the majority of cyclooxygenase-2 and inducible NO synthase was located in the dense network of macrophages resident in the muscularis, which were immunoreactive to ED2. Based on these findings, IL-1␤ acts as an anti-proliferative mediator, which acts indirectly through the production of PGE 2 and NO from resident macrophage within ileal smooth muscle tissue.