Published online before print June 9, 2005, doi: 10.1161/01.ATV.0000172688.26838.9f
© 2005 American Heart Association, Inc.
Vascular Biology |
Type 2 Diabetic Mice Have Increased Arteriolar Tone and Blood Pressure
Enhanced Release of COX-2–Derived Constrictor Prostaglandins
From the Department of Physiology (Z.B., W.L., T.H.N., A.K., G.K.), New York Medical College, Valhalla, NY; the Department of Pathophysiology (A.K.), Semmelweis University, Budapest, Hungary; and the Division of Clinical Physiology Z.B., N.E., A.T.), Institute of Cardiology, University of Debrecen, Debrecen, Hungary.
Correspondence to Zsolt Bagi, MD, PhD, Division of Clinical Physiology, Institute of Cardiology, University of Debrecen, 4004 Debrecen, PO Box 1, Hungary. E-mail bagizs{at}jaguar.unideb.hu
Objective— Type 2 diabetes mellitus (T2-DM) is frequently associated with vascular dysfunction and elevated blood pressure, yet the underlying mechanisms are not completely understood. We hypothesized that in T2-DM, the regulation of peripheral vascular resistance is altered because of changes in local vasomotor mechanisms.
Methods and Results— In mice with T2-DM (C57BL/KsJ-db–/db–), systolic and mean arterial pressures measured by the tail cuff method were significantly elevated compared with those of control (db+/db–) animals (db/db, 146±5 and 106±2 mm Hg versus control, 133±4 and 98±4 mm Hg, respectively; P<0.05). Total peripheral resistance, calculated from cardiac output values (measured by echocardiography) and mean arterial pressure were significantly elevated in db/db mice (db/db, 25±6 versus control, 15±1 mm Hg[middot]mL–1[middot]min–1). In isolated, pressurized gracilis muscle arterioles (diameter 
80 µm) from db/db mice, stepwise increases in intraluminal pressure (from 20 to 120 mm Hg) elicited a greater reduction in diameter than in control vessels at each pressure step (at 80 mm Hg, db/db, 66±4% versus control, 79±3%). The passive diameters of arterioles (obtained in Ca2+-free solution) and the calculated myogenic index were not significantly different in the 2 groups. The presence of the prostaglandin H2/thromboxane A2 receptor antagonist SQ29548 did not affect arteriolar diameters of control mice but reduced the enhanced arteriolar tone of db/db mice back to control levels (at 80 mm Hg, 80±4%). The inhibitor of cyclooxygenase-1 (COX-1), SC-560, did not affect the basal tone of arterioles, whereas NS-398, an inhibitor of COX-2, caused a significant shift in the arteriolar pressure–diameter curve of vessels from db/db mice (at 80 mm Hg, 76±3%) but not in those of control mice. Also, in aortas of db/db mice, expression of COX-2 was enhanced compared with controls.
Conclusions— Collectively, these findings suggest that in mice with T2-DM, the basal tone of skeletal muscle arterioles is increased because of an enhanced COX-2–dependent production of constrictor prostaglandins. These alterations in microvascular prostaglandin synthesis may contribute to the increase in peripheral resistance and blood pressure in T2-DM.
Here we report that mice with type 2 diabetes mellitus have elevated systolic blood pressures and increased peripheral vascular resistance. In type 2 diabetic mice, these alterations are associated with enhanced skeletal muscle arteriolar tone, which is likely attributable to increased release of COX-2–derived constrictor prostaglandins within the arteriolar wall.
Key Words: type 2 diabetes mellitus • microvessels • basal arteriolar tone • cyclooxygenase-2
This article has been cited by other articles:
 |
|
 |
|
  T. Matsumoto, E. Noguchi, K. Ishida, T. Kobayashi, N. Yamada, and K. Kamata Metformin normalizes endothelial function by suppressing vasoconstrictor prostanoids in mesenteric arteries from OLETF rats, a model of type 2 diabetes Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1165 - H1176. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Su, P. A. Lucchesi, R. A. Gonzalez-Villalobos, D. I. Palen, B. M. Rezk, Y. Suzuki, H. A. Boulares, and K. Matrougui Role of Advanced Glycation End Products With Oxidative Stress in Resistance Artery Dysfunction in Type 2 Diabetic Mice Arterioscler. Thromb. Vasc. Biol., August 1, 2008; 28(8): 1432 - 1438. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Belmadani, D. I. Palen, R. A. Gonzalez-Villalobos, H. A. Boulares, and K. Matrougui Elevated Epidermal Growth Factor Receptor Phosphorylation Induces Resistance Artery Dysfunction in Diabetic db/db Mice Diabetes, June 1, 2008; 57(6): 1629 - 1637. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sonoyama, A. Greenstein, A. Price, K. Khavandi, and T. Heagerty Review: Vascular remodeling: implications for small artery function and target organ damage Therapeutic Advances in Cardiovascular Disease, December 1, 2007; 1(2): 129 - 137. [Abstract] [PDF]
|
|
|
|
|
|
A. P. Kellogg, T. D. Wiggin, D. D. Larkin, J. M. Hayes, M. J. Stevens, and R. Pop-Busui Protective Effects of Cyclooxygenase-2 Gene Inactivation Against Peripheral Nerve Dysfunction and Intraepidermal Nerve Fiber Loss in Experimental Diabetes Diabetes, December 1, 2007; 56(12): 2997 - 3005. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Toth, A. Racz, J. Toth, P. M. Kaminski, M. S. Wolin, Z. Bagi, and A. Koller Contribution of polyol pathway to arteriolar dysfunction in hyperglycemia. Role of oxidative stress, reduced NO, and enhanced PGH2/TXA2 mediation Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3096 - H3104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-E. Gendron and E. Thorin A change in the redox environment and thromboxane A2 production precede endothelial dysfunction in mice Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2508 - H2515. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Matsumoto, M. Kakami, E. Noguchi, T. Kobayashi, and K. Kamata Imbalance between endothelium-derived relaxing and contracting factors in mesenteric arteries from aged OLETF rats, a model of Type 2 diabetes Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1480 - H1490. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Yue, T. Arai, M. Terashima, A. Y. Sheikh, F. Cao, D. Charo, G. Hoyt, R. C. Robbins, E. A. Ashley, J. Wu, et al. Magnetic resonance imaging of progressive cardiomyopathic changes in the db/db mouse Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2106 - H2118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Xiang, J. S. Naik, S. R. Abram, and R. L. Hester Chronic hyperglycemia impairs functional vasodilation via increasing thromboxane-receptor-mediated vasoconstriction Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H231 - H236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Erdei, Z. Bagi, I. Edes, G. Kaley, and A. Koller H2O2 increases production of constrictor prostaglandins in smooth muscle leading to enhanced arteriolar tone in Type 2 diabetic mice Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H649 - H656. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Drouin, N. Thorin-Trescases, E. Hamel, J. R. Falck, and E. Thorin Endothelial nitric oxide synthase activation leads to dilatory H2O2 production in mouse cerebral arteries Cardiovasc Res, January 1, 2007; 73(1): 73 - 81. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Szerafin, N. Erdei, T. Fulop, E. T. Pasztor, I. Edes, A. Koller, and Z. Bagi Increased Cyclooxygenase-2 Expression and Prostaglandin-Mediated Dilation in Coronary Arterioles of Patients With Diabetes Mellitus Circ. Res., September 1, 2006; 99(5): e12 - 317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Harris and M. D. Breyer Update on Cyclooxygenase-2 Inhibitors Clin. J. Am. Soc. Nephrol., March 1, 2006; 1(2): 236 - 245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Lizanecz, Z. Bagi, E. T. Pasztor, Z. Papp, I. Edes, N. Kedei, P. M. Blumberg, and A. Toth Phosphorylation-Dependent Desensitization by Anandamide of Vanilloid Receptor-1 (TRPV1) Function in Rat Skeletal Muscle Arterioles and in Chinese Hamster Ovary Cells Expressing TRPV1 Mol. Pharmacol., March 1, 2006; 69(3): 1015 - 1023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Xie, W. Su, Z. Guo, H. Pang, S. R. Post, and M. C. Gong Up-regulation of CPI-17 phosphorylation in diabetic vasculature and high glucose cultured vascular smooth muscle cells Cardiovasc Res, February 1, 2006; 69(2): 491 - 501. [Abstract] [Full Text] [PDF]
|
|