Document Detail


Molecular mechanisms regulating the vascular prostacyclin pathways and their adaptation during pregnancy and in the newborn.
MedLine Citation:
PMID:  22679221     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Prostacyclin (PGI(2)) is a member of the prostanoid group of eicosanoids that regulate homeostasis, hemostasis, smooth muscle function and inflammation. Prostanoids are derived from arachidonic acid by the sequential actions of phospholipase A(2), cyclooxygenase (COX), and specific prostaglandin (PG) synthases. There are two major COX enzymes, COX1 and COX2, that differ in structure, tissue distribution, subcellular localization, and function. COX1 is largely constitutively expressed, whereas COX2 is induced at sites of inflammation and vascular injury. PGI(2) is produced by endothelial cells and influences many cardiovascular processes. PGI(2) acts mainly on the prostacyclin (IP) receptor, but because of receptor homology, PGI(2) analogs such as iloprost may act on other prostanoid receptors with variable affinities. PGI(2)/IP interaction stimulates G protein-coupled increase in cAMP and protein kinase A, resulting in decreased [Ca(2+)](i), and could also cause inhibition of Rho kinase, leading to vascular smooth muscle relaxation. In addition, PGI(2) intracrine signaling may target nuclear peroxisome proliferator-activated receptors and regulate gene transcription. PGI(2) counteracts the vasoconstrictor and platelet aggregation effects of thromboxane A(2) (TXA(2)), and both prostanoids create an important balance in cardiovascular homeostasis. The PGI(2)/TXA(2) balance is particularly critical in the regulation of maternal and fetal vascular function during pregnancy and in the newborn. A decrease in PGI(2)/TXA(2) ratio in the maternal, fetal, and neonatal circulation may contribute to preeclampsia, intrauterine growth restriction, and persistent pulmonary hypertension of the newborn (PPHN), respectively. On the other hand, increased PGI(2) activity may contribute to patent ductus arteriosus (PDA) and intraventricular hemorrhage in premature newborns. These observations have raised interest in the use of COX inhibitors and PGI(2) analogs in the management of pregnancy-associated and neonatal vascular disorders. The use of aspirin to decrease TXA(2) synthesis has shown little benefit in preeclampsia, whereas indomethacin and ibuprofen are used effectively to close PDA in the premature newborn. PGI(2) analogs have been used effectively in primary pulmonary hypertension in adults and have shown promise in PPHN. Careful examination of PGI(2) metabolism and the complex interplay with other prostanoids will help design specific modulators of the PGI(2)-dependent pathways for the management of pregnancy-related and neonatal vascular disorders.
Authors:
Batoule H Majed; Raouf A Khalil
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Review     Date:  2012-06-07
Journal Detail:
Title:  Pharmacological reviews     Volume:  64     ISSN:  1521-0081     ISO Abbreviation:  Pharmacol. Rev.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-04     Completed Date:  2012-12-17     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  0421737     Medline TA:  Pharmacol Rev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  540-82     Citation Subset:  IM    
Affiliation:
Harvard Medical School, Brigham and Women's Hospital, Division of Vascular Surgery, 75 Francis St., Boston, MA 02115, USA.
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MeSH Terms
Descriptor/Qualifier:
Adaptation, Physiological*
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemistry,  pharmacology,  therapeutic use
Cytochrome P-450 Enzyme System / antagonists & inhibitors,  metabolism
Endothelium, Vascular / drug effects,  enzymology,  metabolism
Enzyme Inhibitors / chemistry,  pharmacology,  therapeutic use
Epoprostenol / analogs & derivatives,  biosynthesis*,  pharmacology
Female
Humans
Infant, Newborn
Intramolecular Oxidoreductases / antagonists & inhibitors,  metabolism
Ligands
Pregnancy
Pregnancy Complications, Cardiovascular / enzymology,  metabolism*,  prevention & control
Prostaglandin-Endoperoxide Synthases / metabolism
Receptors, Epoprostenol / agonists,  antagonists & inhibitors,  metabolism*
Signal Transduction*
Thromboxane-A Synthase / antagonists & inhibitors,  metabolism
Vascular Diseases / enzymology,  metabolism*,  prevention & control
Vasodilation / drug effects
Grant Support
ID/Acronym/Agency:
HD60702/HD/NICHD NIH HHS; HL65998/HL/NHLBI NIH HHS; HL98724/HL/NHLBI NIH HHS; R01 HL065998-10/HL/NHLBI NIH HHS; R03 HD060702-02/HD/NICHD NIH HHS; R21 HL098724-02/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/Enzyme Inhibitors; 0/Ligands; 0/Receptors, Epoprostenol; 35121-78-9/Epoprostenol; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.99.1/Prostaglandin-Endoperoxide Synthases; EC 5.3.-/Intramolecular Oxidoreductases; EC 5.3.99.4/prostacyclin synthetase; EC 5.3.99.5/Thromboxane-A Synthase
Comments/Corrections

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