Polacek D, Bech F, McKinsey J F, Davies P F
Department of Surgery, Pritzker School of Medicine, University of Chicago, Ill., USA.
J Vasc Res. 1997 Jan-Feb;34(1):19-30. doi: 10.1159/000159198.
The specialized functions of endothelium require intercellular communication between endothelial cells within the monolayer, and between endothelium and other cells present in the vessel wall. This is accomplished by a combination of paracrine soluble mediators and direct gap-junctional intercellular communication (GJIC) mediated by a family of connexin proteins. A prominent connexin expressed by vascular cells in vivo and in vitro is connexin 43 (Cx43). We have investigated the in vivo gene regulation of Cx43 in the context of vascular pathology, as a result of mechanical injury, hypercholesterolemia or both. The aortoiliac bifurcation in the rabbit was examined following three types of insult: (1) diet-induced hypercholesterolemia resulting in macrophage-rich fatty streak lesions, (2) mechanical, stretch-denudation injury resulting in intimal smooth muscle cell (SMC) proliferation and (3) mechanical injury superimposed on hypercholesterolemia resulting in a complex vascular lesion having characteristics of both interventions. The normal rabbit iliac artery expressed approximately equal levels of Cx43 mRNA in the medial SMC layers and in the endothelium. In hypercholesterolemia-induced atherosclerosis, Cx43 expression was most prominent in macrophage foam cells even though normocholesterolemic precursor monocytes did not express Cx43 mRNA. Antibodies directed specifically to Cx43 protein confirmed the expression of macrophage gap junction protein in these cells. Medial SMC in hypercholesterolemia exhibited less Cx43 than their normal counterparts in control animals. Mechanical injury in the absence of hypercholesterolemia resulted in intimal thickening in which Cx43 expression in the intimal SMC was equivalent to that in the subjacent medial SMC, both being approximately equivalent to normal uninjured rabbit medial SMC expression. Cell-specific expression of Cx43 in combined mechanical injury/hypercholesterolemia was similar to that observed in hypercholesterolemia alone: Cx43 upregulation in macrophages, while medial SMC were downregulated. Normo- and hypercholesterolemic alveolar macrophages of the lung and Kupffer cells of the liver did not exhibit induction of Cx43 mRNA, nor did macrophages isolated from peritoneal or bronchial lavage fluid of the same animals. This work extends our previous finding of Cx43 upregulation in human atherectomy tissue and demonstrates that atherosclerotic lesions in situ, in a controlled animal model of atherosclerosis, exhibit cell-specific changes in Cx43 gene expression. Changes in medial SMC migration, proliferation and phenotype, as well as enhanced interactions between adherent/infiltrating monocytes and endothelium may be related to modified GJIC pathways in the vessel wall.
内皮细胞的特殊功能需要单层内皮细胞之间以及内皮细胞与血管壁中其他细胞之间进行细胞间通讯。这是通过旁分泌可溶性介质与由连接蛋白家族介导的直接间隙连接细胞间通讯（GJIC）相结合来实现的。体内和体外血管细胞表达的一种重要连接蛋白是连接蛋白43（Cx43）。我们研究了在血管病变情况下，由于机械损伤、高胆固醇血症或两者兼而有之导致的Cx43的体内基因调控。对兔的主动脉髂动脉分叉处进行了三种类型损伤后的检查：（1）饮食诱导的高胆固醇血症导致富含巨噬细胞的脂肪条纹病变，（2）机械性拉伸剥脱损伤导致内膜平滑肌细胞（SMC）增殖，（3）叠加在高胆固醇血症上的机械损伤导致具有两种干预特征的复杂血管病变。正常兔髂动脉在内膜平滑肌层和内皮中表达的Cx43 mRNA水平大致相等。在高胆固醇血症诱导的动脉粥样硬化中，Cx43表达在巨噬细胞泡沫细胞中最为突出，尽管正常胆固醇水平的前体单核细胞不表达Cx43 mRNA。特异性针对Cx43蛋白的抗体证实了这些细胞中巨噬细胞间隙连接蛋白的表达。高胆固醇血症中的内膜平滑肌细胞表达的Cx43比对照动物中的正常对应细胞少。在没有高胆固醇血症的情况下，机械损伤导致内膜增厚，其中内膜平滑肌细胞中的Cx43表达与相邻内膜平滑肌细胞中的表达相当，两者都大致相当于正常未受伤兔内膜平滑肌细胞的表达。在机械损伤/高胆固醇血症联合情况下，Cx43的细胞特异性表达与单独高胆固醇血症中观察到的相似：巨噬细胞中Cx43上调，而内膜平滑肌细胞下调。肺的正常和高胆固醇血症肺泡巨噬细胞以及肝的库普弗细胞均未表现出Cx43 mRNA的诱导，从同一动物的腹膜或支气管灌洗液中分离的巨噬细胞也未表现出这种诱导。这项工作扩展了我们之前在人类动脉粥样硬化斑块切除组织中发现的Cx43上调，并表明在动脉粥样硬化的可控动物模型中，原位动脉粥样硬化病变在Cx43基因表达上表现出细胞特异性变化。内膜平滑肌细胞迁移、增殖和表型的变化，以及黏附/浸润单核细胞与内皮之间增强的相互作用可能与血管壁中改变的GJIC途径有关。
