Chang Shurong, Young Bryan D, Li Shijie, Qi Xiaoxia, Richardson James A, Olson Eric N
Department of Molecular Biology, The University of Texas Southwestern Medical Center at Dallas, TX 75390, USA.
Cell. 2006 Jul 28;126(2):321-34. doi: 10.1016/j.cell.2006.05.040.
Development and homeostasis of the cardiovascular system require intimate interactions between endothelial and smooth muscle cells, which form a seamless circulatory network. We show that histone deacetylase 7 (HDAC7) is specifically expressed in the vascular endothelium during early embryogenesis, where it maintains vascular integrity by repressing the expression of matrix metalloproteinase (MMP) 10, a secreted endoproteinase that degrades the extracellular matrix. Disruption of the HDAC7 gene in mice results in embryonic lethality due to a failure in endothelial cell-cell adhesion and consequent dilatation and rupture of blood vessels. HDAC7 represses MMP10 gene transcription by associating with myocyte enhancer factor-2 (MEF2), a direct activator of MMP10 transcription and essential regulator of blood vessel development. These findings reveal an unexpected and specific role for HDAC7 in the maintenance of vascular integrity and have important implications for understanding the processes of angiogenesis and vascular remodeling during cardiovascular development and disease.
心血管系统的发育和稳态需要内皮细胞和平滑肌细胞之间密切的相互作用，它们形成了一个无缝的循环网络。我们发现，组蛋白去乙酰化酶7（HDAC7）在胚胎早期发育过程中特异性地表达于血管内皮中，它通过抑制基质金属蛋白酶（MMP）10的表达来维持血管完整性，MMP10是一种分泌型内蛋白酶，可降解细胞外基质。小鼠中HDAC7基因的破坏会导致胚胎致死，原因是内皮细胞间黏附失败，进而导致血管扩张和破裂。HDAC7通过与肌细胞增强因子2（MEF2）结合来抑制MMP10基因转录，MEF2是MMP10转录的直接激活剂和血管发育的重要调节因子。这些发现揭示了HDAC7在维持血管完整性方面出人意料的特定作用，对于理解心血管发育和疾病过程中的血管生成和血管重塑过程具有重要意义。
