Involvement of transforming growth factor-beta in regulation of calcium transients in diabetic vascular smooth muscle cells.
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-beta1 and -beta2 isoforms to aortic smooth muscle cells in culture and diabetic cells had enhanced production of TGF-beta2. In the in vivo condition, TGF-beta1 was increased in diabetic glomeruli, whereas TGF-beta2 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.
Sharma
Kumar
K
Dorrance Hamilton Research Laboratories, Division of Nephrology, Department of Medicine, Thomas Jefferson University, Suite 353, Jeff Alumni Hall, 1020 Locust Street, Philadelphia, PA 19107, USA. kumar.sharma@jefferson.edu
Deelman
Leo
L
Madesh
Muniswamy
M
Kurz
Bernd
B
Ciccone
Emilio
E
Siva
Senthuran
S
Hu
Taishan
T
Zhu
Yanqing
Y
Wang
Lewei
L
Henning
Robert
R
Ma
Xinliang
X
Hajnoczky
Gyorgy
G
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D006984:Hypertrophy; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007678:Kidney Glomerulus / Q000473:pathology; D008833:Microcirculation; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D014661:Vasoconstriction / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000906:Antibodies; D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D044140:Receptor, Angiotensin, Type 1; D018160:Receptors, Cytoplasmic and Nuclear; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D002118:Calcium