Involvement of transforming growth factor-β in regulation of calcium transients in diabetic vascular smooth muscle cells
Involvement of transforming growth factor-β in regulation of calcium transients in diabetic vascular smooth muscle cells
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DOI：
10.1152/ajprenal.00145.2003
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发表时间：
2003-12-01
影响因子：
4.2
通讯作者：
Hajnoczky, G
中科院分区：
文献类型：
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作者：
Sharma, K;Deelman, L;Hajnoczky, G
血管平滑肌细胞对血管收缩剂的钙瞬变改变可能导致糖尿病血流调节改变。我们推测，糖尿病诱导的转化生长因子（TGF）-β的生产有助于受损血管紧张素Ⅱ反应的血管平滑肌细胞在大血管和微血管。从糖尿病大鼠中分离的主动脉血管平滑肌细胞表现出显著受损的ANG II诱导的胞浆钙[Ca 2 +]信号，其通过抗TGF-β抗体预处理完全恢复。从肾小球前血管分离的微血管平滑肌细胞在高糖培养中也观察到类似的结果。糖尿病对[Ca 2 +]瞬变的影响通过向培养的主动脉平滑肌细胞中加入TGF-β（1）和-β（2）亚型来复制，并且糖尿病细胞增加了TGF-β（2）的产生。在体内条件下，TGF-β（1）在糖尿病肾小球中增加，而TGF-β（2）在糖尿病主动脉中增加。在糖尿病大鼠中发现的肾小球滤过表面积的特征性增加通过用抗TGF-β抗体治疗来防止，并且抗TGF-β抗体完全恢复了糖尿病大鼠中受损的ANG II诱导的主动脉环收缩。受损的血管功能障碍可能部分是由于减少的肌醇1，4，5-三磷酸受体（IP 3R），因为在糖尿病主动脉中发现减少的I型IP 3R表达并通过抗TGF-β抗体恢复。我们的结论是，TGF-β通过抑制血管平滑肌细胞中的钙瞬变在早期糖尿病的血管功能障碍中起着重要作用。
Altered calcium [Ca2+] transients of vascular smooth muscle cells to vasoconstrictors may contribute to altered regulation of blood flow in diabetes. We postulated that diabetes-induced transforming growth factor (TGF)-beta production contributes to impaired ANG II response of vascular smooth muscle cells in macrovessels and microvessels. Aortic vascular smooth muscle cells isolated from diabetic rats exhibited markedly impaired ANG II-induced cytosolic calcium [Ca2+] signal that was completely restored by pretreatment with anti-TGF-beta antibodies. Similar findings were noted in microvascular smooth muscle cells isolated from preglomerular vessels and cultured in high glucose. The impact of diabetes on [Ca2+] transients was replicated by addition of TGF-beta(1) and -beta(2) isoforms to aortic smooth muscle cells in culture and diabetic cells had enhanced production of TGF-beta(2). In the in vivo condition, TGF-beta(1) was increased in diabetic glomeruli, whereas TGF-beta(2) was increased in diabetic aorta. The characteristic increase in glomerular filtration surface area found in diabetic rats was prevented by treatment with anti-TGF-beta antibodies, and impaired ANG II-induced aortic ring contraction in diabetic rats was completely restored by anti-TGF-beta antibodies. Impaired vascular dysfunction may be partly due to decreased inositol 1,4,5-trisphosphate receptor (IP3R), as reduced type I IP3R expression was found in diabetic aorta and restored by anti-TGF-beta antibodies. We conclude that TGF-beta plays an important role in the vascular dysfunction of early diabetes by inhibiting calcium transients in vascular smooth muscle cells.