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

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.