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Hypoxic Vasospasm Mediated by cIMP: When Soluble Guanylyl Cyclase Turns Bad
Yuansheng Gao1, Zhengju Chen, Susan W S Leung
1*Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China; †State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China; ‡Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; and §State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.
Journal of Cardiovascular Pharmacology
|September 30, 2014
Summary
Hypoxia causes blood vessel contraction, amplified by inosine 3′,5′-cyclic monophosphate (cIMP) and Rho kinase (ROCK). This discovery offers new therapeutic targets for cardiovascular diseases like hypertension and stroke.
Area of Science:
- Cardiovascular Physiology
- Molecular Pharmacology
Background:
- Hypoxia induces acute vasoconstriction in isolated blood vessels.
- This effect, termed hypoxic augmentation of vasoconstriction, is nitric oxide-dependent and involves soluble guanylyl cyclase activation.
Purpose of the Study:
- To elucidate the intracellular mechanisms underlying hypoxic augmentation of vasoconstriction.
- To investigate the role of inosine 3′,5′-cyclic monophosphate (cIMP) in mediating hypoxic vasoconstriction.
Main Methods:
- Studied isolated blood vessel preparations under hypoxic conditions.
- Measured intracellular levels of inosine 5'-triphosphate and synthesis of cIMP.
- Assessed the impact of exogenous cIMP and inosine 5'-triphosphate on vasoconstriction.
- Determined Rho kinase (ROCK) activity in response to hypoxia and cIMP.
Main Results:
- Hypoxic vasoconstriction is associated with increased intracellular inosine 5'-triphosphate and cIMP synthesis.
- Exogenous cIMP and inosine 5'-triphosphate augmented hypoxic vasoconstriction.
- Hypoxic and cIMP-evoked vasoconstriction correlated with increased ROCK activity, suggesting cIMP sensitizes myofilaments to Ca2+ via ROCK.
Conclusions:
- cIMP plays a crucial role in mediating hypoxic augmentation of vasoconstriction, potentially through ROCK activation.
- Understanding the cIMP pathway offers novel therapeutic targets for cardiovascular diseases linked to exaggerated vasoconstriction, such as coronary artery disease, myocardial infarction, hypertension, and stroke.
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