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in Regulation of Calcium Transients in Diabetic Vascular Smooth Muscle Cells
1 Department of Medicine, Dorrance Hamilton Research Laboratories, Division of NephrologyThomas Jefferson University, Philadelphia, PA, USA
2 Department of Clinical Pharmacology, University of Groningen, Groningen, The Netherlands
3 Department of Anatomy, Pathology and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
4 Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: kumar.sharma{at}mail.tju.edu.
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 TGF-
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 pre-treatment with anti-TGF- antibodies. Similar findings were noted in microvascular smooth muscle cells isolated from pre-glomerular vessels and cultured in high glucose. The impact of diabetes on [Ca2+] transients was replicated by addition of TGF-1 and -2 isoforms to aortic smooth muscle cells in culture and diabetic cells had enhanced production of TGF-2. In the in vivo condition, TGF-1 was increased in diabetic glomeruli whereas TGF-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- antibodies and impaired Ang II-induced aortic ring contraction in diabetic rats was completely restored by anti-TGF- antibodies. Impaired vascular dysfunction may be partly due to decreased inositol 1,4,5-trisphosphate receptor, as reduced type I IP3R expression was found in diabetic aorta and restored by anti-TGF- antibodies. We conclude that TGF- plays an important role in the vascular dysfunction of early diabetes by inhibiting calcium transients in vascular smooth muscle cells.
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