Regulation of ET-1 biosynthesis in cerebral microvascular endothelial cells by vasoactive agents and PKC

Momoh A. Yakubu, Charles Leffler

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38 Citations (Scopus)

Abstract

Endothelin-1 (ET-1) is the most potent vasoconstrictor agent known. ET- 1 is elevated in the cerebrospinal fluid following hemorrhage and brain injury and can compromise cerebral microvascular homeostasis. The modulation of ET-1 production by cerebral microvascular endothelial cells and the mechanism by which such changes take place are very important in our understanding of the pathological roles of ET-1. In the present study, we investigated the effects of vasoconstrictor agents that can be released from hemolyzed blood, cAMP-dependent dilators, and the role of protein kinase C (PKC) in the regulation of ET-1 production by piglet cerebral microvascular endothelial cells in culture. ET-1 was measured by RIA. 1) Cerebral microvascular endothelial cells synthesize and release ET-1 into the media; 2) 5-hydroxytryptamine (5-HT), lysophosphatidic acid (LPA), thromboxane analog U-46619, fetal bovine serum (20%), and phorbol 12-myristate 13- acetate significantly increase ET-1 production; 3) basal and vasoconstrictor agent-induced increases in ET-1 production by endothelial cells may be mediated via PKC; 4) cAMP-dependent vasodilators attenuate the basal production of ET-1 by cerebral microvessels; and 5) pretreatment of endothelial cells with a higher concentration of LPA, U-46619, or 5-HT counterbalances the cAMP-dependent dilator agent-induced reduction in basal ET-1 production. Therefore, by-products of hemolyzed blood can stimulate the production of ET-1 by a PKC-mediated mechanism. cAMP-dependent dilators can attenuate the vasoconstrictor agent-induced elevation in ET-1 production. These results suggest that cerebral microvascular homeostasis could be compromised by effects of interactions among vasoactive agents released during conditions injurious to the brain and they may further the understanding of potential contributions of hemolyzed blood clots to subarachnoid hemorrhage-induced vasospasm.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume276
Issue number2 45-2
StatePublished - 1999

Fingerprint

Biosynthesis
Endothelial cells
Endothelin-1
Protein Kinase C
Endothelial Cells
Vasoconstrictor Agents
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Blood
Brain
Serotonin
Homeostasis
Cerebrospinal fluid
Thromboxanes
Subarachnoid Hemorrhage
Microvessels
Vasodilator Agents
Cell culture
Brain Injuries
Byproducts
Cerebrospinal Fluid

All Science Journal Classification (ASJC) codes

  • Cell Biology
  • Clinical Biochemistry
  • Physiology
  • Physiology (medical)

Cite this

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title = "Regulation of ET-1 biosynthesis in cerebral microvascular endothelial cells by vasoactive agents and PKC",
abstract = "Endothelin-1 (ET-1) is the most potent vasoconstrictor agent known. ET- 1 is elevated in the cerebrospinal fluid following hemorrhage and brain injury and can compromise cerebral microvascular homeostasis. The modulation of ET-1 production by cerebral microvascular endothelial cells and the mechanism by which such changes take place are very important in our understanding of the pathological roles of ET-1. In the present study, we investigated the effects of vasoconstrictor agents that can be released from hemolyzed blood, cAMP-dependent dilators, and the role of protein kinase C (PKC) in the regulation of ET-1 production by piglet cerebral microvascular endothelial cells in culture. ET-1 was measured by RIA. 1) Cerebral microvascular endothelial cells synthesize and release ET-1 into the media; 2) 5-hydroxytryptamine (5-HT), lysophosphatidic acid (LPA), thromboxane analog U-46619, fetal bovine serum (20{\%}), and phorbol 12-myristate 13- acetate significantly increase ET-1 production; 3) basal and vasoconstrictor agent-induced increases in ET-1 production by endothelial cells may be mediated via PKC; 4) cAMP-dependent vasodilators attenuate the basal production of ET-1 by cerebral microvessels; and 5) pretreatment of endothelial cells with a higher concentration of LPA, U-46619, or 5-HT counterbalances the cAMP-dependent dilator agent-induced reduction in basal ET-1 production. Therefore, by-products of hemolyzed blood can stimulate the production of ET-1 by a PKC-mediated mechanism. cAMP-dependent dilators can attenuate the vasoconstrictor agent-induced elevation in ET-1 production. These results suggest that cerebral microvascular homeostasis could be compromised by effects of interactions among vasoactive agents released during conditions injurious to the brain and they may further the understanding of potential contributions of hemolyzed blood clots to subarachnoid hemorrhage-induced vasospasm.",
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AU - Yakubu, Momoh A.

AU - Leffler, Charles

PY - 1999

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N2 - Endothelin-1 (ET-1) is the most potent vasoconstrictor agent known. ET- 1 is elevated in the cerebrospinal fluid following hemorrhage and brain injury and can compromise cerebral microvascular homeostasis. The modulation of ET-1 production by cerebral microvascular endothelial cells and the mechanism by which such changes take place are very important in our understanding of the pathological roles of ET-1. In the present study, we investigated the effects of vasoconstrictor agents that can be released from hemolyzed blood, cAMP-dependent dilators, and the role of protein kinase C (PKC) in the regulation of ET-1 production by piglet cerebral microvascular endothelial cells in culture. ET-1 was measured by RIA. 1) Cerebral microvascular endothelial cells synthesize and release ET-1 into the media; 2) 5-hydroxytryptamine (5-HT), lysophosphatidic acid (LPA), thromboxane analog U-46619, fetal bovine serum (20%), and phorbol 12-myristate 13- acetate significantly increase ET-1 production; 3) basal and vasoconstrictor agent-induced increases in ET-1 production by endothelial cells may be mediated via PKC; 4) cAMP-dependent vasodilators attenuate the basal production of ET-1 by cerebral microvessels; and 5) pretreatment of endothelial cells with a higher concentration of LPA, U-46619, or 5-HT counterbalances the cAMP-dependent dilator agent-induced reduction in basal ET-1 production. Therefore, by-products of hemolyzed blood can stimulate the production of ET-1 by a PKC-mediated mechanism. cAMP-dependent dilators can attenuate the vasoconstrictor agent-induced elevation in ET-1 production. These results suggest that cerebral microvascular homeostasis could be compromised by effects of interactions among vasoactive agents released during conditions injurious to the brain and they may further the understanding of potential contributions of hemolyzed blood clots to subarachnoid hemorrhage-induced vasospasm.

AB - Endothelin-1 (ET-1) is the most potent vasoconstrictor agent known. ET- 1 is elevated in the cerebrospinal fluid following hemorrhage and brain injury and can compromise cerebral microvascular homeostasis. The modulation of ET-1 production by cerebral microvascular endothelial cells and the mechanism by which such changes take place are very important in our understanding of the pathological roles of ET-1. In the present study, we investigated the effects of vasoconstrictor agents that can be released from hemolyzed blood, cAMP-dependent dilators, and the role of protein kinase C (PKC) in the regulation of ET-1 production by piglet cerebral microvascular endothelial cells in culture. ET-1 was measured by RIA. 1) Cerebral microvascular endothelial cells synthesize and release ET-1 into the media; 2) 5-hydroxytryptamine (5-HT), lysophosphatidic acid (LPA), thromboxane analog U-46619, fetal bovine serum (20%), and phorbol 12-myristate 13- acetate significantly increase ET-1 production; 3) basal and vasoconstrictor agent-induced increases in ET-1 production by endothelial cells may be mediated via PKC; 4) cAMP-dependent vasodilators attenuate the basal production of ET-1 by cerebral microvessels; and 5) pretreatment of endothelial cells with a higher concentration of LPA, U-46619, or 5-HT counterbalances the cAMP-dependent dilator agent-induced reduction in basal ET-1 production. Therefore, by-products of hemolyzed blood can stimulate the production of ET-1 by a PKC-mediated mechanism. cAMP-dependent dilators can attenuate the vasoconstrictor agent-induced elevation in ET-1 production. These results suggest that cerebral microvascular homeostasis could be compromised by effects of interactions among vasoactive agents released during conditions injurious to the brain and they may further the understanding of potential contributions of hemolyzed blood clots to subarachnoid hemorrhage-induced vasospasm.

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