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Dissertation
Intracellular regulation of sustained contraction stimulated by L-type Ca²⁺ channel activation in swine carotid smooth muscle
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2016
DOI:
https://doi.org/10.17918/etd-7150
Abstract
Sustained vascular smooth muscle (VSM) contraction is important for maintaining systemic blood pressure. A chronic increase in VSM contraction raises blood pressure, a condition known as hypertension. L-type Ca²⁺ channels (LTCCs) on the surface of VSM cells are believed to contribute to sustained contraction, however the intracellular signaling downstream of LTCCs is unclear thus limiting the opportunity to develop targeted therapies for hypertension. The purpose of this project was to determine how prolonged force is sustained in VSM downstream of LTCC activation. Intact VSM tissue was contracted with an LTCC agonist, Bay K8644. Inhibitors against LTCC activity and downstream kinases of interest- myosin light chain (MLC) kinase, p42/44 mitogen-activated protein (MAP) kinase, protein kinase C (PKC), Rho kinase (ROCK), and p21-activated kinase (PAK1)- were used to elucidate signaling that maintains long-term force. Surprisingly, the known modulatory pathways of VSM contraction by calcium sensitization and thin filament regulation were not activated during sustained contraction. The most intriguing finding was that inhibition of MAP kinase led to a significant increase in Bay K8644-induced force and MLC phosphorylation, while inhibition of MLC kinase resulted in significantly increased MAP kinase activity. The ubiquitous signaling kinase PAK1 was investigated as a possible mediator for the observed effects between MLC kinase and MAP kinase. Inhibiting PAK1 decreased MLC phosphorylation, MAP kinase phosphorylation, and force. The collective results suggest the presence of a novel force regulatory mechanism involving PAK1 and its effects on p42/44 MAP kinase and MLC kinase during prolonged force stimulated by LTCC opening.
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Details
- Title
- Intracellular regulation of sustained contraction stimulated by L-type Ca²⁺ channel activation in swine carotid smooth muscle
- Creators
- Hillevi K. Ets - DU
- Contributors
- Robert S. Moreland (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 7150; 991014632601404721