Chen S J, Li H, Durand J, Oparil S, Chen Y F
Division of Cardiovascular Disease, University of Alabama at Birmingham 35294-0007, USA.
Circulation. 1996 Feb 1;93(3):577-84. doi: 10.1161/01.cir.93.3.577.
Vascular disease progresses more slowly in females with functional ovaries than in males. The mechanisms of this vasoprotective effect of female sex are incompletely understood. This study tested (1) whether there is a sex difference in the development of myointimal proliferation after balloon injury of the rat carotid artery in vivo, (2) whether this response is estrogen or androgen dependent, and (3) whether there is a sexual dimorphism in expression of the c-myc proto-oncogene in intact and/or damaged rat carotid arteries.
Ten-week-old male and female Sprague-Dawley rats were either gonadectomized or studied intact. Gonadectomized rats of both sexes were implanted with estradiol, testosterone, or nothing (control) 3 days before vascular injury. Two weeks later, the rats were killed by overdose of pentobarbital, and the injured right and uninjured control left carotid arteries were fixed and subjected to morphometric analysis for evaluation of the degree of myointimal thickening. Separate groups of intact male and female rats were killed at 1 and 2 hours after vascular injury, and total RNA from injured and uninjured vessels was subjected to Northern blot analysis for assessment of steady state c-myc mRNA levels. Neointimal area and the ratio of neointimal to medial area were significantly less in intact female rats than in intact male rats (P < .05). Gonadectomy of female rats was associated with a greater increase in neointima formation after balloon injury than that observed in intact females (P < .05), but testosterone replacement did not further enhance this response. Estradiol treatment significantly inhibited myointimal proliferation after vascular injury in gonadectomized rats of both sexes (P < .05). Neither gonadectomy nor gonadectomy plus testosterone replacement altered the myointimal proliferative response to balloon injury in male rats. Steady state c-myc mRNA levels were detectable in undamaged carotid arteries in intact rats of both sexes and were significantly greater in males than in females; c-myc mRNA levels were increased in both sexes after carotid injury, but the response was significantly larger in magnitude and more rapid in males than in females.
These data indicate that the sex difference in myointimal proliferation after vascular injury is estrogen dependent. C-myc gene expression is greater in the undamaged carotid artery of the male than in that of the female, and the responsiveness of this gene to balloon injury of the artery is more rapid and more robust in the male than in the female rat. These findings have direct implications for the prevention and treatment of vascular disease in humans.
具有功能正常卵巢的女性血管疾病进展比男性更缓慢。女性性别这种血管保护作用的机制尚未完全明确。本研究检测了：（1）在体内大鼠颈动脉球囊损伤后肌内膜增殖发展过程中是否存在性别差异；（2）这种反应是否依赖雌激素或雄激素；（3）在完整和/或受损的大鼠颈动脉中，原癌基因c-myc的表达是否存在性别二态性。
将10周龄的雄性和雌性Sprague-Dawley大鼠进行去势或保留性腺研究。去势的两性大鼠在血管损伤前3天植入雌二醇、睾酮或不植入任何物质（对照）。两周后，过量戊巴比妥钠处死大鼠，将受伤的右侧和未受伤的对照左侧颈动脉固定，进行形态学分析以评估肌内膜增厚程度。在血管损伤后1小时和2小时处死单独分组的完整雄性和雌性大鼠，从受伤和未受伤血管提取总RNA，进行Northern印迹分析以评估c-myc mRNA稳态水平。完整雌性大鼠的新生内膜面积以及新生内膜与中膜面积之比显著小于完整雄性大鼠（P < 0.05）。雌性大鼠去势后球囊损伤后新生内膜形成的增加幅度大于完整雌性大鼠（P < 0.05），但睾酮替代并未进一步增强这种反应。雌二醇治疗显著抑制了去势两性大鼠血管损伤后的肌内膜增殖（P < 0.05）。去势以及去势加睾酮替代均未改变雄性大鼠对球囊损伤后的肌内膜增殖反应。在两性完整大鼠未受损的颈动脉中均可检测到c-myc mRNA稳态水平，且雄性大鼠中的水平显著高于雌性；颈动脉损伤后两性的c-myc mRNA水平均升高，但雄性大鼠的反应幅度显著更大且速度更快。
这些数据表明血管损伤后肌内膜增殖的性别差异是依赖雌激素的。雄性大鼠未受损颈动脉中c-myc基因表达高于雌性，并且该基因对动脉球囊损伤的反应在雄性大鼠中比雌性大鼠更迅速、更强烈。这些发现对人类血管疾病的预防和治疗具有直接意义。
