Charles W. Leffler, Ph.D., Professor
Department of Physiology & Biophysics

The gas, carbon monoxide (CO), is produced physiologically by catabolism of heme via heme oxygenase. One of the isoforms of heme oxygenase, HO-2, is expressed in highest concentration in the brain where it resides in neurons, vascular endothelium and smooth muscle. It generates CO from cellular heme. Our research is based on preliminary data that suggest carbon monoxide (CO) is an endogenous mediator in the newborn cerebral circulation. These preliminary data include detection of heme oxygenase 2 (HO-2) in the cerebral vasculature, cerebrovascular dilator responses to exogenously applied CO and to heme oxygenase substrate, and measurements of CO production by cerebral microvessels and endothelium. The likelihood that CO will prove to be a physiologically significant intercellular messenger molecule is high.

We hypothesize that CO is an integral component of microvascular control in neonatal cerebral circulation. To test this three specific aims are being addressed in vivo (pigs) and in vitro (cells isolated from newborn pigs in primary culture). The first is the functional significance of CO in regulation of cerebral microvascular tone; localize and characterize heme oxygenase of the neonatal cerebral vasculature and ; investigate mechanisms of CO induced modifications of cerebral microvascular tone.

Recent Publications

COX-1 and COX-2 contributions to basal and IL-1B-stimulated prostanoid synthesis in human neonatal cerebral microvascular endothelial cells. Parfenova H, Levine V, Gunther WM, Pourcyrous M and Leffler CW. Pediatr Res 52:342-348, 2002.

Carbon monoxide dilates cerebral arterioles by enhancing the coupling of Ca2+ sparks to KCa channels. Jaggar JH, Leffler, CW, Cheranov D, Tcheranova SE and Cheng X. Circ Res 91:610-617, 2002.

L-type voltage-dependent Ca2+ channels in cerebral microvascular endothelial cells and ET-1 biosynthesis. Am J Physiol 283:C1687-C1695, 2002.

Ionotropic glutamate receptors in cerebral microvascular endothelium are functionally linked to heme oxygenase. Parfenova H, Fedinec A and Leffler CW. J Cerebral Blood Flow Metab 23:190-197, 2003.

Carbon monoxide as an attenuator of vasoconstriction in piglet cerebral circulation. Winestone JS, Bonner C and Leffler CW. Experimental Biology and Medicine 228:46-50, 2003.

Helena Parfenova, Ph.D., Professor
Department of Physiology & Biophysics

 

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