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(Stroke. 2009;40:930.)
© 2009 American Heart Association, Inc.

Original Contributions

Roles of Glia Limitans Astrocytes and Carbon Monoxide in Adenosine Diphosphate-Induced Pial Arteriolar Dilation in Newborn Pigs

From Laboratory for Research in Neonatal Physiology, Department of Physiology, University of Tennessee Health Science Center, Memphis, Tenn.

Correspondence to Dr Charles W. Leffler, Department of Physiology, 894 Union Ave, Memphis, TN 38163. E-mail cleffler{at}physio1.utmem.edu

Background and Purpose— Astrocytes, neurons, and microvessels together form a neurovascular unit allowing blood flow to match neuronal activity. Adenosine diphosphate (ADP) is an important signaling molecule in the brain, and dilation in response to ADP is astrocyte-dependent in rats and newborn pigs. Carbon monoxide (CO), produced endogenously by catabolism of heme to CO, iron, and biliverdin via heme oxygenase, is an important cell-signaling molecule in the neonatal cerebral circulation. We hypothesize ADP stimulates CO production by glia limitans astrocytes and that this CO causes pial arteriolar dilation.

Methods— Experiments were performed using anesthetized piglet with closed cranial windows, and freshly isolated piglet astrocytes and microvessels. Astrocyte injury was caused by topical application of L-2-alpha aminoadipic acid (2 mmol/L, 5 hours). Cerebrospinal fluid was collected from under the cranial windows for measurement of ADP-stimulated CO production. CO was measured by gas chromatography-mass spectroscopy analysis.

Results— Before, but not after, astrocyte injury in vivo, topical ADP stimulated both CO production and dilation of pial arterioles. Astrocyte injury did not block dilation to isoproterenol or bradykinin. Chromium mesoporphyrin, an inhibitor of heme oxygenase, also prevented the ADP-induced increase in cerebrospinal fluid CO and pial arteriolar dilation caused by ADP, but not dilation to sodium nitroprusside. ADP also increased CO production by freshly isolated piglet astrocytes and cerebral microvessels, although the increase was smaller in the microvessels.

Conclusions— These data suggest that glia limitans astrocytes use CO as a gasotransmitter to cause pial arteriolar dilation in response to ADP.

Key Words: carbon monoxide • cerebral circulation • glia • newborn • toxin