Yamasaki Masao, Kawai Junsuke, Nakaoka Takashi, Ogita Teruhiko, Tojo Akihiro, Fujita Toshiro
Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Hypertension. 2003 Feb;41(2):302-7. doi: 10.1161/01.hyp.0000050645.11117.9e.
Adrenomedullin (AM) inhibits vascular smooth muscle cell proliferation stimulated by fetal calf serum and platelet-derived growth factor in vitro. In this study, an adenovirus expressing AM (AxCAAM) was created to examine the in vivo action of AM. Femoral arteries of Wistar rats were wrapped with a silicone cuff and treated with adenovirus expressing Escherichia coli beta-galactosidase (AxCALacZ) or AxCAAM. Immunoreactivity for endothelial nitric oxide synthase (eNOS) was reduced in the endothelium of cuff-injured arteries and was associated with increased local DNA synthesis. Consequently, the intimal formation measured by the intimal-to-medial ratio was significantly increased at 14 and 28 days after the cuff placement. AxCAAM-infected arteries increased the expression of eNOS in the endothelium and inducible NOS in the media and the adventitia. AxCAAM significantly decreased the intimal-to-medial ratio by 40% at 14 days and 51% at 28 days, whereas AxCALacZ showed no changes compared with cuff-injured control arteries. AM overexpression effectively limits intimal hyperplasia by reducing cell proliferation through a nitric oxide-dependent pathway of eNOS. Our findings suggest the possibility of a therapeutic use of the AM gene for the prevention of vascular proliferative disorders.
肾上腺髓质素（AM）在体外可抑制胎牛血清和血小板衍生生长因子刺激的血管平滑肌细胞增殖。在本研究中，构建了一种表达AM的腺病毒（AxCAAM），以研究AM的体内作用。用硅胶套包裹Wistar大鼠的股动脉，并用表达大肠杆菌β-半乳糖苷酶的腺病毒（AxCALacZ）或AxCAAM进行处理。在套扎损伤动脉的内皮中，内皮型一氧化氮合酶（eNOS）的免疫反应性降低，且与局部DNA合成增加相关。因此，在套扎后14天和28天，以内膜与中膜比值衡量的内膜形成显著增加。AxCAAM感染的动脉增加了内皮中eNOS以及中膜和外膜中诱导型NOS的表达。AxCAAM在14天时使内膜与中膜比值显著降低40%，在28天时降低51%，而与套扎损伤的对照动脉相比，AxCALacZ组无变化。AM的过表达通过eNOS的一氧化氮依赖性途径减少细胞增殖，有效限制内膜增生。我们的研究结果提示了AM基因在预防血管增殖性疾病方面治疗应用的可能性。
