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Vascular Smooth Muscle Cells Contracted and Relaxed Diagram

VSMC Inflammatory Response In Atherosclerosis Research

Smooth Muscle Cell Function

Smooth muscle cells (SMCs) are specialized cells found especially in hollow organs with contractile function like the arteries and bladder. Contraction and relaxation of SMCs regulates organ function; for example, in the cardiovascular system, where SMCs are called vascular SMCs (VSMCs), VSMC contraction narrows blood vessels to constrict blood flow, while relaxation dilates blood vessels to enhance blood flow. VSMCs also play an important role in response to vessel injury—they are able to proliferate and migrate to sites of vessel damage, where they adopt a pro-inflammatory phenotype. Importantly, dysregulation of VSMC function, particularly in cardiovascular diseases like atherosclerosis, can activate this pro-inflammatory function and contribute to disease pathogenesis.

Interested in SMCs for your research? Check out the Lifeline® catalog, which contains SMCs from multiple tissue types, including:

Lifeline® SMCs are optimized for growth in Vasculife® medium, which does not contain phenol red or antimicrobials.

Lifeline® VSMCs in Atherosclerosis Research

Worldwide, deaths due to cardiovascular disease eclipse even those due to cancer. One of the major causes of cardiovascular disease is atherosclerosis, a condition that occurs when plaque accumulates in arteries, causing a narrowing of the arteries and increasing the risk for heart attack or stroke. As part of the pathogenesis of atherosclerosis, inflammatory signals stimulate proinflammatory responses from VSMCs, which in turn, may exacerbate the disease. In a 2016 study, Herman and colleagues (opens in new window) set out to investigate the role of stress granules in the VSMC inflammatory response that occurs in atherosclerosis. They hypothesized that stress granules (cellular stress-induced aggregates that develop in the cytoplasm) form in response to atherosclerotic conditions and are associated with disease progression.

To test this hypothesis, the group first determined whether the presence of atherosclerosis would induce stress granule formation in vivo. Using a mouse model prone to atherosclerosis and fed a western diet, they found that levels of the Ras GTPase-activating protein SH3 domain-binding protein (G3BP1)—a stress granule marker—built up in VMSCs and macrophages in atherosclerotic plaques after 12-16 weeks of exposure to a western diet.

Next, using Lifeline® coronary artery VSMCs, the group assessed how stress granules formed in response to various forms of cellular stress. Their data showed that stress granules formed in response to mitochondrial stress induced by clotrimazole, the stress granule stimulus arsenite, and oxidized low-density lipoprotein (oxLDL), which is present in high levels during atherosclerosis. They also found that oxLDL induced stress granule formation in bone marrow-derived macrophages, isolated from wild-type mice.

The authors then tested VSMC stress granule formation in other models, including in a mouse model of vascular restenosis and in human coronary artery tissue samples from patients with failing hearts. They found that mice with vascular restenosis displayed increased stress granule formation in synthetic neointimal VMSCs, and VSMCs in coronary artery tissue from human patients with failing hearts had significantly higher levels of poly-A-binding protein (a stress granule marker) compared with healthy coronary artery samples.

Given the role of cytoskeletal components in stress granule localization and transport, the researchers next investigated whether the cytoskeleton was involved in stress granule formation in VSMCs. They treated Lifeline® VSMCs with the calpain inhibitor zLLal (known to disrupt microtubule dynamics) and clotrimazole, a stress granule inducer. They found that VSMCs treated with zLLal and clotrimazole had significantly fewer stress granules than cells induced with clotrimazole alone.

Importantly, treatment with the anti-inflammatory cytokine IL-9 before stress granule induction with clotrimazole significantly decreased stress granule formation and reduced expression of stress granule markers. To assess whether G3BP1 is required for stress granule function in VSMCs, the authors knocked down G3BP1, and as expected, VSMCs lacking G3BP1 had fewer stress granules following induction with clotrimazole. Finally, the authors demonstrated that VSMCs lacking G3BP1 expressed lower levels of mRNAs involved in proliferation and inflammation.

Together, the results of this study suggest that vascular inflammatory and stress stimuli induce stress granule formation in VSMCs and anti-inflammatory intervention may decrease this effect.

How do you use Lifeline® cell products in your research? Let us know and we could feature your study here on our next blog!

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