Β8 Integrins Are Required for Vascular Morphogenesis in Mouse Embryos (original) (raw)
Related papers
Vascular Development of the Brain Requires β8 Integrin Expression in the Neuroepithelium
The Journal of Neuroscience, 2005
We showed previously that loss of the integrin β8 subunit, which forms αvβ8 heterodimers, results in abnormal vascular development in the yolk sac, placenta, and brain. Animals lacking the integrin β8 (itgβ8) gene die either at midgestation, because of insufficient vascularization of the placenta and yolk sac, or shortly after birth with severe intracerebral hemorrhage. To specifically focus on the role of integrins containing the β8 subunit in the brain, and to avoid early lethalities, we used a targeted deletion strategy to deleteitgβ8only from cell types within the brain. Ablatingitgβ8from vascular endothelial cells or from migrating neurons did not result in cerebral hemorrhage. Targeted deletion ofitgβ8from the neuroepithelium, however, resulted in bilateral hemorrhage at postnatal day 0, although the phenotype was less severe than initgβ8-null animals. Newborn mice lackingitgβ8from the neuroepithelium had hemorrhages in the cortex, ganglionic eminence, and thalamus, as well as...
Molecular and Cellular Biology, 2008
The largest subgroup of integrins is that containing the 1 subunit. 1 integrins have been implicated in a wide array of biological processes ranging from adhesion to cell growth, organogenesis, and mechanotransduction. Global deletion of 1 integrin expression results in embryonic death at ca. embryonic day 5 (E5), a developmental time point too early to determine the effects of this integrin on vascular development. To elucidate the specific role of 1 integrin in the vasculature, we conditionally deleted the 1 gene in the endothelium. Homozygous deletion of 1 integrins in the endothelium resulted in failure of normal vascular patterning, severe fetal growth retardation, and embryonic death at E9.5 to 10, although there were no overt effects on vasculogenesis. Heterozygous endothelial 1 gene deletion did not diminish fetal or postnatal survival, but it reduced 1 subunit expression in endothelial cells from adult mice by approximately 40%. These mice demonstrated abnormal vascular remodeling in response to experimentally altered in vivo blood flow and diminished vascularization in healing wounds. These data demonstrate that endothelial expression of 1 integrin is required for developmental vascular patterning and that endothelial 1 gene dosing has significant functional effects on vascular remodeling in the adult. Understanding how 1 integrin expression is modulated may have significant clinical importance.
2008
The largest subgroup of integrins is that containing the 1 subunit. 1 integrins have been implicated in a wide array of biological processes ranging from adhesion to cell growth, organogenesis, and mechanotransduction. Global deletion of 1 integrin expression results in embryonic death at ca. embryonic day 5 (E5), a developmental time point too early to determine the effects of this integrin on vascular development. To elucidate the specific role of 1 integrin in the vasculature, we conditionally deleted the 1 gene in the endothelium. Homozygous deletion of 1 integrins in the endothelium resulted in failure of normal vascular patterning, severe fetal growth retardation, and embryonic death at E9.5 to 10, although there were no overt effects on vasculogenesis. Heterozygous endothelial 1 gene deletion did not diminish fetal or postnatal survival, but it reduced 1 subunit expression in endothelial cells from adult mice by approximately 40%. These mice demonstrated abnormal vascular remodeling in response to experimentally altered in vivo blood flow and diminished vascularization in healing wounds. These data demonstrate that endothelial expression of 1 integrin is required for developmental vascular patterning and that endothelial 1 gene dosing has significant functional effects on vascular remodeling in the adult. Understanding how 1 integrin expression is modulated may have significant clinical importance.
Endothelial β1 integrins regulate sprouting and network formation during vascular development
Development, 2010
b1 integrins are important regulators of vascular differentiation and development, as their endothelial-specific deletion results in embryonic lethality. In the present study, we investigated the molecular mechanisms underlying the prominent vascular abnormalities that occur in the absence of b1 integrins. Because of the early embryonic lethality of knockout mice, we studied endothelial cell and vessel development in b1-integrin-deficient murine embryonic stem cells to gain novel insights into the role of b1 integrins in vasculo-angiogenesis. We found that vessel development was strongly defective in the mutant embryoid bodies (EBs), as only primitive and short sprouts developed from clusters of vascular precursors in b1 integrin -/-EBs, whereas complex network formation of endothelial tubes was observed in wild-type EBs. The vascular defect was due to deficient b1 integrin expression in endothelial cells, as its endothelial-specific re-expression rescued the phenotype entirely. The mechanism responsible for defective vessel formation was found to be reduced endothelial cell maturation, migration and elongation. Moreover, the lower number of endothelial cells in b1 integrin -/-EBs was due to an increased apoptosis versus proliferation rate. The enhanced apoptosis and proliferation of b1 integrin -/endothelial cells was related to the elevation of peNOS and pAKT signaling molecules, respectively. Our data demonstrate that endothelial b1 integrins are determinants of vessel formation and that this effect is mediated via different signaling pathways.
Developmental Biology, 2006
Blood vessel development is in part regulated by pericytes/presumptive vascular smooth muscle cells (PC/pvSMCs). Here, we demonstrate that interactions between PC/pvSMCs and extracellular matrix play a critical role in this event. We show that the cranial vessels in α4 integrin-deficient mouse embryos at the stage of vessel remodeling are increased in diameter. This defect is accompanied by a failure of PC/pvSMCs, which normally express α4β1 integrin, to spread uniformly along the vessels. We also find that fibronectin but not VCAM-1 is localized in the cranial vessels at this stage. Furthermore, cultured α4 integrin-null PC/pvSMCs plated on fibronectin display a delay in initiating migration, a reduction in migration speed, and a decrease in directional persistence in response to a polarized force of shear flow. These results suggest that specific motile activities of PC/pvSMCs regulated by mechanical signals imposed by the interstitial extracellular matrix may also be required in vivo for the distribution and function of the PC/pvSMCs during blood vessel development.
Cell Communication and Adhesion, 2003
Integrins are a family of cell surface molecules that mediate the attachment of cells to the extracellular matrix (ECM). These αβ heterodimers are involved in many biological processes. We used northern blotting and in situ hybridization to study the pattern of β3 integrin gene expression during mouse embryogenesis. Northern blotting detected two species of β3 mRNA from 7 to 17 days post coitum (dpc). These transcripts were abundant in the adult testis, kidney, liver, spleen, and heart. In situ hybridization experiments detected high levels of β3 in the major haematopoietic and lymphoid organs: yolk sac, liver, and thymus. Moreover, β3 transcripts were also detected in the vascular system, where β3 integrin probably plays a key role in angiogenesis and vasculogenesis. We also detected a hybridization signal in the gut, the bronchioles of the lungs, and the bladder wall. β3 transcripts were also present in the medullary regions of the adrenal glands and in the developing skeleton. Our study shows that β3 gene expression is not restricted to the liver and gut during mouse development. We also detected β3 integrin mRNA in the yolk sac, vessels, lung, bladder, and developing bones. Our data suggest that β3 integrin plays a key role in many important physiological processes like haematopoiesis, angiogenesis, phagocytosis, and bone resorption. embryogenesis (21). Integrins are αβ heterodimers, and β3 is one of eight known β subunits. It associates with the αIIb or αv subunit (31, 32). The α and β3 subunits are synthesized from separate mRNAs. The β3 subunit associates with proα, a single-chain precursor of the α subunit, in the endoplasmic reticulum. The proαβ3 complex is then 129 130 L. LE GAT ET AL.
Placental Defects in α7 Integrin Null Mice
Placenta, 2007
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.
Life Sciences, 2017
Persistent fetal vasculature (PFV) occurs as a result of a failure of fetal vasculature to undergo normal programmed involution. During development, before the formation of retinal vessels, the lens and the inner retina are nourished by the hyaloid vasculature. Hyaloid vessels extend from the optic nerve and run through the vitreous to encapsulate the lens. As fetal retinal vessels develop, hyaloid vasculature naturally regresses. Failure of regression of the hyaloid artery has been shown to lead to severe congenital pathologies. Studies on childhood blindness and visual impairment in the United States have shown that PFV accounts for 4.8% of total blindness. Although PFV is a serious developmental disease affecting the normal visual development pathway, the exact regulatory mechanism responsible for the regression of the hyaloid artery is still unknown. In this review, we have summarized the cellular defects associated with different knockout models that manifest features of persistent fetal vasculature. Based on similar cellular defects observed in different knockouts (KO)s such as altered migration, increased proliferation and decreased apoptosis and, the known role of integrins in the regulation of these cellular behaviors, we propose here that integrins may play a significant role in the pathophysiology of persistent fetal vasculature disease.
Reduced Expression of Integrin αvβ8 Is Associated with Brain Arteriovenous Malformation Pathogenesis
The American journal of …, 2010
Brain arteriovenous malformations (BAVMs) are a rare but potentially devastating hemorrhagic disease. Transforming growth factor-β signaling is required for proper vessel development, and defective transforming growth factor-β superfamily signaling has been implicated in BAVM pathogenesis. We hypothesized that expression of the transforming growth factor-β activating integrin, αvβ8, is reduced in BAVMs and that decreased β8 expression leads to defective neoangiogenesis. We determined that β8 protein expression in perivascular astrocytes was reduced in human BAVM lesional tissue compared with controls and that the angiogenic response to focal vascular endothelial growth factor stimulation in adult mouse brains with local Cre-mediated deletion of itgb8 and smad4 led to vascular dysplasia in newly formed blood vessels. In addition, common genetic variants in ITGB8 were associated with BAVM susceptibility, and ITGB8 genotypes associated with increased risk of BAVMs correlated with decreased β8 immunostaining in BAVM tissue. These three lines of evidence from human studies and a mouse model suggest that reduced expression of integrin β8 may be involved in the pathogenesis of sporadic BAVMs.