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Ba2+-Induced Vasoconstriction as a Model to Investigate the Dynamin Dependence of Biological Processes Regulating
Mariangela Gentile1, Alice Panti1, Eugenio Paccagnini1
1Department of Life Sciences, University of Siena, Siena, Italy.
Abstract:
Understanding the mechanisms underpinning vascular smooth muscle contraction, which are critical targets for cardiovascular disease treatment, is essential for developing novel therapeutic agents. Recently, the role of mitochondrial fission as a key modulatory event in the vascular contractile process has been questioned. Therefore, the present study, conducted on ex vivo rat aorta rings, aimed to elucidate its role. As mitochondrial dynamics is a Ca2+-dependent process, experiments were performed using preparations incubated in a Ca2+-free medium, depleted of sarcoplasmic reticulum Ca2+ content, and stimulated by Ba2+. Contractile responses evoked by Ba2+, either alone or in the presence of phenylephrine or (S)-(-)-Bay K 8644, occurred without mitochondrial fission. Furthermore, hallmarks of mitochondrial fusion were observed in rings stimulated by Ba2+ alone. The Drp1 inhibitors mdivi-1 and dynasore antagonized Ba2+-induced contraction, whereas the dynasore analogue dyngo-4a and the dynamin stimulator ryngo 1-23 synergized with Ba2+-induced contraction. All tested compounds, except mdivi-1, induced mitochondrial fission, with particularly pronounced effects observed with dynasore. Similar results were obtained in rings stimulated by Ba2+ in the presence of either phenylephrine or (S)-(-)-Bay K 8644. In conclusion, these findings indicate that rat aorta contraction can occur independently of mitochondrial fission. Moreover, Ba2+, used in place of Ca2+ as a vasoconstricting agent, provides a valuable experimental framework for identifying off-target effects of dynamin modulators.
Insights
Vascular smooth muscle contraction can occur without mitochondrial fission, challenging previous assumptions. Barium ions (Ba2+) offer a new method to study vasoconstriction and dynamin modulators.
Area of Science:
- Cardiovascular Physiology
- Mitochondrial Biology
- Pharmacology
Background:
- Vascular smooth muscle contraction is crucial for cardiovascular health and a target for drug development.
- The role of mitochondrial fission in vascular contraction is debated.
- Mitochondrial dynamics are calcium (Ca2+)-dependent.
Purpose of the Study:
- To investigate the role of mitochondrial fission in ex vivo rat aorta ring contraction.
- To explore the utility of barium ions (Ba2+) as a calcium (Ca2+) substitute in studying vascular contraction.
- To assess the impact of dynamin modulators on vascular contraction and mitochondrial dynamics.
Main Methods:
- Experiments were conducted on ex vivo rat aorta rings.
- Preparations were made Ca2+-free and sarcoplasmic reticulum Ca2+ depleted.
- Rings were stimulated with Ba2+ alone or with phenylephrine or (S)-(-)-Bay K 8644.
- Mitochondrial fission/fusion and contractile responses were assessed.
- Drp1 inhibitors (mdivi-1, dynasore) and dynamin modulators (dyngo-4a, ryngo 1-23) were used.
Main Results:
- Ba2+-evoked contractions occurred without mitochondrial fission; mitochondrial fusion was observed with Ba2+ alone.
- Drp1 inhibitors partially blocked Ba2+-induced contraction.
- Dynamin modulators and some Drp1 inhibitors induced mitochondrial fission.
- Ba2+-stimulated contractions, even with phenylephrine or (S)-(-)-Bay K 8644, were independent of mitochondrial fission.
Conclusions:
- Rat aorta contraction can proceed independently of mitochondrial fission.
- Ba2+ serves as a useful tool to induce vasoconstriction without relying on intracellular Ca2+ stores.
- This Ba2+-based model is valuable for identifying off-target effects of dynamin modulators.
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