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Elevated plasma catecholamines functionally compensate for the reduced myogenic tone in smooth muscle STIM1 knockout
Prahalathan Pichavaram1, Wen Yin1,2, Kirk W Evanson1
1Department of Physiology, University of Tennessee Health Sciences Center, 71 South Manassas Street, Memphis, TN 38163, USA.
Insights
Stromal interaction molecule 1 (STIM1) deletion in smooth muscle impairs vascular integrity and alters blood pressure regulation. Despite maintained blood pressure, STIM1 deficiency leads to cardiac dysfunction due to increased sympathetic activity.
Area of Science:
- Vascular biology
- Cardiovascular physiology
- Cellular biology
Background:
- Stromal interaction molecule 1 (STIM1) regulates smooth muscle cell growth and proliferation.
- STIM1 is crucial for maintaining vascular integrity.
- The role of STIM1 in vascular structure and function requires further investigation.
Purpose of the Study:
- To investigate the role of STIM1 in vascular integrity.
- To determine if reduced STIM1 expression affects vascular structure and function.
- To evaluate the impact of STIM1 deficiency on blood pressure.
Main Methods:
- Generated smooth muscle-specific STIM1 knockout (sm-STIM1 KO) mice.
- Assessed myogenic reactivity and vasoconstrictor responses in mesenteric arteries.
- Monitored blood pressure and heart rate via telemetry.
- Measured plasma catecholamine levels.
- Analyzed cytoskeletal structure in cultured smooth muscle cells.
- Evaluated responses to Ang II-induced hypertension.
Main Results:
- sm-STIM1 KO mice exhibited reduced STIM1 protein expression and impaired myogenic reactivity.
- Elevated heart rate and plasma catecholamine levels were observed in sm-STIM1 KO mice.
- Cytoskeletal defects in smooth muscle cells and altered arterial mechanical properties were noted.
- sm-STIM1 KO mice were protected from Ang II-induced hypertension but developed cardiac fibrosis and dysfunction.
Conclusions:
- STIM1 deletion in smooth muscle compromises arterial mechanical properties and myogenic tone.
- Compensatory sympathetic activation in sm-STIM1 KO mice leads to detrimental cardiac effects.
- STIM1 is essential for maintaining vascular homeostasis and cardiac function.
Aims:
Stromal interaction molecule 1 (STIM1) has emerged as an important player in the regulation of growth and proliferation of smooth muscle cells. Therefore, we hypothesized that STIM1 plays a crucial role in the maintenance of vascular integrity. The objective of this study was to evaluate whether reduced expression of STIM1 could modify the structure and function of the vasculature, leading to changes in blood pressure (BP).
Methods And Results:
Smooth muscle-specific STIM1 knockout (sm-STIM1 KO) in mice resulted in arteries with ∼80% reduced STIM1 protein expression as compared with control mice. Mesenteric vessels exposed to increasing transmural pressure revealed attenuated myogenic reactivity and reduced vasoconstrictor response to phenylephrine in sm-STIM1 KO arteries. BP monitored via telemetry in sm-STIM1 KO and matched controls did not reveal differences. However, heart rate was significantly increased in sm-STIM1 KO mice. Consistent with these findings, plasma catecholamine levels were higher in sm-STIM1 KO than in control mice. Increased sympathetic activity in sm-STIM1 KO mice was unmasked by apha1-adrenergic receptor inhibitor (prazosin) and by treatment with the ganglion-blocking agent, hexamethonium. Both treatments resulted in a greater reduction of BP in sm-STIM1 KO mice. Cytoskeleton of cultured smooth muscle cells was studied by immunocytochemistry using specific antibodies. Staining for actin and vinculin revealed significant alterations in the cytoskeletal architecture of cells isolated from sm-STIM1 KO arteries. Finally, although sm-STIM1 KO mice were protected from Ang II-induced hypertension, such treatment resulted in significant fibrosis and a rapid deterioration of cardiac function.
Conclusions:
STIM1 deletion in smooth muscle results in attenuated myogenic tone and cytoskeletal defects with detrimental effects on the mechanical properties of arterial tissue. Although BP is maintained by elevated circulating catecholamine, this compensatory stimulation has a deleterious long-term effect on the myocardium.
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