Geary R L, Williams J K, Golden D, Brown D G, Benjamin M E, Adams M R
Department of Surgery, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27157-1095, USA.
Arterioscler Thromb Vasc Biol. 1996 Jan;16(1):34-43. doi: 10.1161/01.atv.16.1.34.
Animal models of arterial injury have failed to predict effective therapy to prevent restenosis in humans. While this may relate to species differences in the control of smooth muscle cell growth, many studies have used nonatherosclerotic animals, thereby failing to consider the importance of atherosclerosis in the response to injury. In an attempt to model human restenosis more accurately, we characterized the response to angioplasty in atherosclerotic monkeys. Twenty-one cynomolgus monkeys were fed an atherogenic diet for 36 months (plasma cholesterol, 12 +/- 1 mmol/L [470 +/- 23 mg/dL]). Angioplasty was then performed in the left iliac artery. After 4, 7, 14, or 28 days, bromodeoxyuridine was given to label proliferating cells, and iliac arteries were fixed in situ at physiological pressure (5 or 6 animals at each time point). Comparisons were made between injured and uninjured iliac arteries within each animal. Angioplasty often fractured the intimal plaque and media, transiently increasing lumen caliber (4 days: lumen area, 232.5 +/- 80.3% of control) and artery size as reflected by external elastic lamina area (EEL). EEL and lumen caliber returned to baseline by 7 days. Proliferation was increased throughout the artery wall at 4 and 7 days and later declined to control rates (4 days, injured versus uninjured: adventitia, 45.0 +/- 6.2% versus 16.3 +/- 7.2%; media, 8.6 +/- 2.6% versus 0.6 +/- 0.1%; intima, 16.0 +/- 5.6% versus 7.8 +/- 3.1%). The intima thickened markedly from 14 to 28 days, but an increase in EEL generally prevented further loss of the short-term gain in lumen caliber (28 days, percent of control: intimal area, 342.8 +/- 88.9%; EEL area, 150.2 +/- 28.9%; lumen area, 119.3 +/- 21.3%). The response to angioplasty in atherosclerotic monkeys appears to closely resemble that in humans. Plaque fracture, delayed recoil, intimal hyperplasia, and remodeling may each be important in determining late lumen caliber. This primate model should prove valuable in defining cellular and biochemical mediators of human restenosis.
动脉损伤的动物模型未能预测出预防人类再狭窄的有效疗法。虽然这可能与平滑肌细胞生长控制方面的物种差异有关，但许多研究使用的是非动脉粥样硬化动物，因此未能考虑动脉粥样硬化在损伤反应中的重要性。为了更准确地模拟人类再狭窄，我们对动脉粥样硬化猴子血管成形术的反应进行了特征描述。21只食蟹猴接受致动脉粥样硬化饮食36个月（血浆胆固醇，12±1 mmol/L[470±23 mg/dL]）。然后对左髂动脉进行血管成形术。在4、7、14或28天后，给予溴脱氧尿苷标记增殖细胞，并在生理压力下将髂动脉原位固定（每个时间点5或6只动物）。对每只动物中受伤和未受伤的髂动脉进行比较。血管成形术常使内膜斑块和中膜破裂，使管腔内径短暂增加（4天时：管腔面积，为对照的232.5±80.3%），并且动脉大小如由外弹性膜面积（EEL）所反映的那样也增加。EEL和管腔内径在7天时恢复到基线水平。在4天和7天时，整个动脉壁的增殖增加，随后下降至对照水平（4天时，受伤与未受伤相比：外膜，45.0±6.2%对16.3±7.2%；中膜，8.6±2.6%对0.6±0.1%；内膜，16.0±5.6%对7.8±3.1%）。内膜从14天到28天显著增厚，但EEL的增加通常可防止管腔内径的短期增加进一步丧失（28天时，对照百分比：内膜面积，342.8±88.9%；EEL面积，150.2±28.9%；管腔面积，119.3±21.3%）。动脉粥样硬化猴子对血管成形术的反应似乎与人类的反应非常相似。斑块破裂、延迟回缩、内膜增生和重塑可能在决定晚期管腔内径方面都很重要。这个灵长类动物模型在确定人类再狭窄的细胞和生化介质方面应该会被证明是有价值的。
