Institute of Physiology I, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
Development. 2010 Mar;137(6):993-1002. doi: 10.1242/dev.045377.
beta1 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 beta1 integrins. Because of the early embryonic lethality of knockout mice, we studied endothelial cell and vessel development in beta1-integrin-deficient murine embryonic stem cells to gain novel insights into the role of beta1 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 beta1 integrin(-/-) EBs, whereas complex network formation of endothelial tubes was observed in wild-type EBs. The vascular defect was due to deficient beta1 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 beta1 integrin(-/-) EBs was due to an increased apoptosis versus proliferation rate. The enhanced apoptosis and proliferation of beta1 integrin(-/-) endothelial cells was related to the elevation of peNOS and pAKT signaling molecules, respectively. Our data demonstrate that endothelial beta1 integrins are determinants of vessel formation and that this effect is mediated via different signaling pathways.
β1 整合素是血管分化和发育的重要调节因子，因为其内皮细胞特异性缺失会导致胚胎致死。在本研究中，我们研究了在缺乏β1 整合素的情况下发生的明显血管异常的分子机制。由于 knockout 小鼠的早期胚胎致死性，我们研究了β1 整合素缺陷型鼠胚胎干细胞中的内皮细胞和血管发育，以深入了解β1 整合素在血管生成中的作用。我们发现，突变体胚体（EBs）中的血管发育严重缺陷，因为只有原始和短的芽从β1 整合素缺陷型 EBs 的血管前体细胞簇中发育，而在野生型 EBs 中观察到内皮管的复杂网络形成。血管缺陷是由于内皮细胞中β1 整合素表达不足所致，因为其内皮细胞特异性重新表达完全挽救了表型。发现导致血管形成缺陷的机制是内皮细胞成熟、迁移和伸长减少。此外，β1 整合素缺陷型 EBs 中内皮细胞数量减少是由于凋亡率相对于增殖率增加所致。β1 整合素缺陷型内皮细胞的凋亡增加和增殖增加与 peNOS 和 pAKT 信号分子的升高有关。我们的数据表明，内皮细胞β1 整合素是血管形成的决定因素，这种作用是通过不同的信号通路介导的。
