Sustained Contraction in Vascular Smooth Muscle by Activation of L-type Ca2+ Channels Does Not Involve Ca2+ Sensitization or Caldesmon

Tissue engineering has emerged as a promising approach to viable small-diameter vascular grafts that may be used to treat cardiovascular diseases. One challenge in constructing such blood vessels is proper localization of endothelial cells and smooth muscle cells, as well as promotion of their cellular functions to generate functional tissues. Thus far, construction of small-diameter vascular substitutes with both endothelial and muscular tissues, which is essential for the grafts to acquire antithrombosis function and sufficient strength to avoid thrombus formation as well as to withstand blood pressure, has not yet been demonstrated. In this study, we engineer small-diameter blood vessel grafts containing both functional endothelial and muscular cell layers, which has been demonstrated in vivo in a living rat model. Our construction of the blood vessel grafts uses vascular-tissue-derived extracellular matrix bioinks and a reservoir-assisted triple-coaxial cell printing technique. The prematured vessel was implanted for three weeks as a graft of rat abdominal aorta in a proof-of-concept study where all implants showed great patency, intact endothelium, remodeled smooth muscle, and integration with host tissues at the end of the study. These outcomes suggest that our approach to tissue-engineered biomimetic blood vessels provides a promising route for the construction of durable small-diameter vascular grafts that may be used in future treatments of cardiovascular diseases.

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Tissue-engineering of vascular grafts containing endothelium and smooth-muscle using triple-coaxial cell printing

Gao

Kim

et al. 2019

Applied Physics Reviews

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Potentiation of active force by cyclic strain in sheep carotid arterial smooth muscle

Wang,

Dong,

Chitano

et al. 2023

Journal of Applied Physiology

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The ability to generate force in large arteries is known to be augmented by cyclic strain that mimics the mechanically dynamic in vivo environment associated with blood pressure fluctuation experienced by these arteries. Cyclic strain does not induce a contractile response, like that observed in the myogenic response seen in small arteries, but prompts a substantial increase of the response to electrical stimulation. We coined this phenomenon "force potentiation". Because protein kinase C (PKC) and rho-kinase (ROCK) are known to play a role in increasing contractility of arterial smooth muscle by inhibition of myosin light chain phosphatase, and integrin-link kinase (ILK) is crucial in mechano-transduction, we examined how inhibition of these kinases affected force potentiation in sheep carotid artery. We found that phosphorylation of the regulatory myosin light chain was enhanced by cyclic strain, but the enhancement was observed only in activated, not in relaxed muscle. Inhibition of ROCK diminished force potentiation and active isometric force, likely due to the dis-inhibition of myosin light chain phosphatase. Inhibition of PKC abolished force potentiation without an effect on active force, suggesting a more exclusive role of PKC (compared with ROCK) in mediating force potentiation. Inhibition of ILK had a similar effect as PKC inhibition, suggesting that ILK may be an upstream kinase for PKC activation by mechanical stimuli. Taken together, the findings suggest that ILK, PKC, and ROCK are important kinases in the signal transduction pathway that mediates the effect of mechanical strain on force potentiation.

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Moderate-Intensity Exercise Training Reduces Vasorelaxation of Mesenteric Arteries: Role of BKCa Channels and Nitric Oxide

et al. 2022

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Exercise training (ET) is well established to induce vascular adaptations on the metabolically active muscles. These adaptations include increased function of vascular potassium channels and enhanced endothelium-dependent relaxations. However, the available data on the effect of ET on vasculatures that normally constrict during exercise, such as mesenteric arteries (MA), are scarce and not conclusive. Therefore, this study hypothesized that 10 weeks of moderate-intensity ET would result in adaptations towards more vasoconstriction or/and less vasodilatation of MA. Young Fischer 344 rats were randomly assigned to a sedentary group (SED; n=24) or exercise training group (EXE; n=28). The EXE rats underwent a progressive treadmill ET program for 10 weeks. Isometric tensions of small (SED; 252.9±29.5 µm, EXE; 248.6±34.4 µm) and large (SED; 397.7±85.3 µm, EXE; 414.0±86.95 µm) MA were recorded in response to cumulative phenylephrine concentrations (PE; 0-30 µM) in the presence and absence of the BKCa channel blocker, Iberiotoxin (100 nM). In another set of experiments, tensions in response to cumulative concentration-response curves of acetylcholine (ACh) or sodium nitroprusside (SNP) were obtained, and pEC50s were compared. Immunoblotting was performed to measure protein expression levels of the BKCa channel subunits and eNOS. ET did not alter the basal tension of small and large MA but significantly increased their responses to PE, and reduced the effect of BKCa channels in opposing the contractile responses to PE without changes in the protein expression level of BKCa subunits. ET also elicited a size-dependent functional adaptations that involved reduced endothelium-independent and endothelium-dependent relaxations. In large MA the sensitivity to SNP was decreased more than in small MA suggesting impaired nitric oxide (NO)-dependent mechanisms within the vascular smooth muscle cells of ET group. Whereas the shift in pEC50 of ACh-induced relaxation of small MA would suggest more effect on the production of NO within the endothelium, which is not changed in large MA of ET group. However, the eNOS protein expression level was not significantly changed between the ET and SED groups. In conclusion, our results indicate an increase in contraction and reduced relaxation of MA after 10 weeks of ET, an adaptation that may help shunt blood flow to metabolically active tissues during acute exercise.

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Sustained Contraction in Vascular Smooth Muscle by Activation of L-type Ca2+ Channels Does Not Involve Ca2+ Sensitization or Caldesmon

Cited by 3 publications

References 48 publications

Tissue-engineering of vascular grafts containing endothelium and smooth-muscle using triple-coaxial cell printing

Tissue-engineering of vascular grafts containing endothelium and smooth-muscle using triple-coaxial cell printing

Potentiation of active force by cyclic strain in sheep carotid arterial smooth muscle

Moderate-Intensity Exercise Training Reduces Vasorelaxation of Mesenteric Arteries: Role of BKCa Channels and Nitric Oxide

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