血管紧张素II和胰岛素诱导睫状动脉平滑肌生长：AT1/AT2拮抗剂的作用

Angiotensin II and insulin induce growth of ciliary artery smooth muscle: effects of AT1/AT2 antagonists.

作者信息

Dubey R K, Flammer J, Lüscher T F

机构信息

Department of Research, University Hospital, Basel, Switzerland.

出版信息

Invest Ophthalmol Vis Sci. 1998 Oct;39(11):2067-75.

PMID:9761285

Abstract

PURPOSE

Abnormal growth of smooth muscle cells (SMCs) in small arteries of the eye is associated with hypertension and diabetes, and the complications that they induce. Migration and proliferation of SMCs into the intima are primary mechanisms involved in neointima formation. In aortic SMCs, angiotensin II (AII)-induced proliferation is inhibited by angiotensin type 1 (AT1) receptor antagonist. However, in small artery SMCs, in particular in the circulation of the eye, the effects of AII on migration and proliferation are unknown.

METHODS

The effects of AII (10(-6) to 10(-10) M) on migration and proliferation of growth-arrested SMCs of porcine ciliary arteries were studied in the presence and absence of insulin (5 x 10(-10) M) by assaying DNA synthesis (3H-thymidine incorporation), cell number, and movement of SMCs across the membrane of a modified Boyden chamber.

RESULTS

In the absence of insulin, only high concentrations (10(-6) to 10(-8) M) of AII induced DNA synthesis and increased cell number (P < 0.05); however, in the presence of insulin (5 x 10(-10) M), AII induced DNA synthesis and cell number at low concentrations (10(-10) M) and in a concentration-dependent manner (P < 0.05). In contrast to proliferation, AII induced SMC migration in a concentration-dependent manner in the absence of insulin (P < 0.05). The AT1 antagonist CGP48933 (10(-8) to 10(-12) M), but not the AT2 antagonist CGP42112 (10(-8) to 10(-12) M), inhibited AII (10(-8) M)-induced proliferation and migration in a concentration-dependent manner (P < 0.05).

CONCLUSIONS

Our results suggest that AII is a potent mitogen for SMCs of ophthalmic arteries, an effect that is enhanced in the presence of insulin, and that it may be an important contributor to structural vascular changes in the ophthalmic circulation in hypertension associated with non-insulin dependent diabetes. The inhibition of AII-induced growth by an AT1 antagonist suggests that these drugs may be important therapeutic tools to prevent structural vascular changes in the ophthalmic vasculature under these conditions.

摘要

目的

眼部小动脉中平滑肌细胞（SMC）的异常生长与高血压、糖尿病及其引发的并发症相关。SMC向内膜的迁移和增殖是参与新生内膜形成的主要机制。在主动脉平滑肌细胞中，血管紧张素II（AII）诱导的增殖受到血管紧张素1型（AT1）受体拮抗剂的抑制。然而，在小动脉平滑肌细胞中，尤其是在眼部循环中，AII对迁移和增殖的影响尚不清楚。

方法

通过检测DNA合成（3H-胸腺嘧啶核苷掺入）、细胞数量以及SMC穿过改良博伊登小室膜的移动情况，研究了在有无胰岛素（5×10⁻¹⁰ M）存在的情况下，AII（10⁻⁶至10⁻¹⁰ M）对猪睫状动脉生长停滞的SMC迁移和增殖的影响。

结果

在无胰岛素的情况下，只有高浓度（10⁻⁶至10⁻⁸ M）的AII能诱导DNA合成并增加细胞数量（P < 0.05）；然而，在有胰岛素（5×10⁻¹⁰ M）存在的情况下，AII在低浓度（10⁻¹⁰ M）时就能诱导DNA合成和细胞数量增加，且呈浓度依赖性（P < 0.05）。与增殖情况相反，在无胰岛素的情况下，AII以浓度依赖性方式诱导SMC迁移（P < 0.05）。AT1拮抗剂CGP48933（10⁻⁸至10⁻¹² M），而非AT2拮抗剂CGP42112（10⁻⁸至10⁻¹² M），以浓度依赖性方式抑制AII（10⁻⁸ M）诱导的增殖和迁移（P < 0.05）。