Vascular spasm is a poorly understood phenomenon with considerable pathologic implications. In our laboratory, we discovered two different mechanisms of vascular spasm that affect the coronary arteries. In the first model, we found that a targeted disruption of the SUR2 genes lead to vascular spasm and cardiac arrhythmias. In this case, SUR2 null mice developed repeated vascular spasm accompanied by changes on the surface electrocardiogram. Using the calcium channel antagonist, we were able to successfully reduce coronary artery vasospasm. Mice with mutant SUR2 serve as a model for Prinzmetal variant angina. The SUR2 gene encodes a protein that binds sulfonylurea agents. These agents are commonly used to treat diabetes. Our work suggests a mechanism for enhanced cardiovascular morbidity from the use of sulfonylurea agents.
The second mechanism of vascular spasm arises from defects extrinsic to vascular smooth muscle. Mice mutant for the sarcoglycan components develop focal degeneration throughout their hearts. It has been suggested that these focal defects arise from vascular spasm. We found that vascular spasm occurs in mice lacking sarcoglycan, but that this spasm arises from a vascular smooth muscle cell extrinsic mechanism. Transgenic restoration of the cardiomyocyte sarcoglycan complex in sarcoglycan null mice corrects vascular spasm.
Chutkow, W. A., J. L. Pu, M. T. Wheeler, J. C. Makielski, C. F. Burant and E. M. McNally. Prinzmetal like vasospasm, hypertension and early death result from mutant Sur2 KATP channels in mice. (2002) J. Clin. Invest. 110: 203-208.
Wheeler, M.T., M.J. Allikian, A. Heydeman, M. Hadhazy, S. Zarnegar and E. M. McNally. Smooth muscle cell extrinsic vascular spasm arises from cardiomyocyte degeneration in sarcoglycan mutant cardiomyopathy. J Clin Invest. (2004) 113:668-75.
Wheeler, M. T., C. E. Korcarz, K. A. Collins, K. A. Lapidos, A. A. Hack, M. R Lyons, S. Zarnegar, J. U. Earley, R. M. Lang and E. M. McNally. Prevention of secondary vasospasm limits cardiomyopathy progression. (2004) Am. J. Pathol. 164:1063-71.
Heydemann, A., Huber, J. M., Kakkar, R., Wheeler, M. T., and McNally, E. M. Functional nitric oxide synthase mislocalization in cardiomyopathy. J Mol Cell Cardiol 2004; 36:213-223.