The dystrophin glycoprotein complex links laminin in the extracellular matrix to the cell cytoskeleton. Loss of dystrophin causes Duchenne muscular dystrophy, the most common human X-chromosome-linked genetic disease. The α7β1 integrin is a second transmembrane laminin receptor expressed in skeletal muscle. Mutations in the α7 integrin gene cause congenital myopathy in humans and mice. The α7β1 integrin is increased in the skeletal muscle of Duchenne muscular dystrophy patients and mdx mice. This observation has led to the suggestion that dystrophin and α7β1 integrin have complementary functional and structural roles. To test this hypothesis, we generated mice lacking both dystrophin and α7 integrin (mdx/α7-/-). The mdx/α7-/- mice developed early-onset muscular dystrophy and died at 2-4 weeks of age. Muscle fibers from mdx/α7-/- mice exhibited extensive loss of membrane integrity, increased centrally located nuclei and inflammatory cell infiltrate, greater necrosis and increased muscle degeneration compared to mdx or α7-integrin null animals. In addition, loss of dystrophin and/or α7 integrin resulted in altered expression of laminin-α2 chain. These results point to complementary roles for dystrophin and α7β1 integrin in maintaining the functional integrity of skeletal muscle.

The ␣7␤1 integrin is a laminin receptor that has been implicated in muscle disease and the development of neuromuscular and myotendinous junctions. Studies have shown the ␣7␤1 integrin is also expressed in nonskeletal muscle tissues. To identify the expression pattern of the ␣7 integrin in these tissues during embryonic development, ␣7 integrin chain knockout mice were generated by a LacZ knockin strategy. In these mice, expression from the ␣7 promoter is reported by ␤-galactosidase. From embryonic day (ED) 11.5 to ED14.5, ␤-galactosidase was detected in the developing central and peripheral nervous systems and vasculature. The loss of the ␣7 integrin gene resulted in partial embryonic lethality. Several ␣7 null embryos were identified with cerebrovascular hemorrhages and showed reduced vascular smooth muscle cells and cerebral vascularization. The ␣7 null mice that survived to birth exhibited vascular smooth muscle defects, including hyperplasia and hypertrophy. In addition, altered expression of ␣5 and ␣6B integrin chains was detected in the cerebral arteries of ␣7 null mice, which may contribute to the vascular phenotype. Our results demonstrate for the first time that the ␣7␤1 integrin is important for the recruitment or survival of cerebral vascular smooth muscle cells and that this integrin plays an important role in vascular development and integrity. Developmental Dynamics 234:11-21, 2005.

Conjugated linoleic acid (CLA) has been the subject of extensive investigation regarding its possible benefits on a variety of human diseases. In some animal studies, CLA has been shown to have a beneficial effect on sclerotic lesions associated with atherosclerosis, be a possible anti-carcinogen, increase feed efficiency, and act as a lean body mass supplement. However, the results have been inconsistent, and the effects of CLA on atherogenesis appear to be dose-, isomer-, tissue-, and species-specific. Similarly, CLA trials in humans have resulted in conflicting findings. Both the human and animal study results may be attributed to contrasting doses of CLA, isomers, the coexistence of other dietary fatty acids, length of study, and inter-and/or intra-species diversities. Recent research advances have suggested the importance of CLA isomers in modulating gene expression involved in oxidative damage, fatty acid metabolism, immune/inflammatory responses, and ultimately atherosclerosis. Although the possible mechanisms of action of CLA have been suggested, they have yet to be determined.

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The α7β1 integrin is a heterodimeric transmembrane receptor that links laminin in the extracellular matrix to the cell cytoskeleton. Loss of the α7 integrin chain results in partial embryonic lethality. We have previously shown that α7 integrin null embryos exhibit vascular smooth muscle cell defects that result in cerebral vascular hemorrhaging. Since the placenta is highly vascularized, we hypothesized that placental vascular defects in α7 integrin null embryos may contribute to the partial embryonic lethality. Placentae from embryonic day (ED) 9.5 and 13.5 α7 integrin knockout embryos showed structural defects including infiltration of the spongiotrophoblast layer into the placental labyrinth, a reduction in the placental labyrinth and loss of distinct placental layers. Embryos and placentae that lacked the α7 integrin weighed less compared to wild-type controls. Blood vessels within the placental labyrinth of α7 integrin null embryos exhibited fewer differentiated vascular smooth muscle cells compared to wild-type. Loss of the α7 integrin resulted in altered extracellular matrix deposition and reduced expression of α5 integrin. Together our results confirm a role for the α7β1 integrin in placental vascular development and demonstrate for the first time that loss of the α7 integrin results in placental defects.