Vascular Smooth Muscle Cells Regulate Vessel Homeostasis and Dysfunction

Vascular smooth muscle cells (VSMCs) are found in blood vessel walls and regulate various aspects of vessel homeostasis, including contraction, dilation, and vessel remodeling. VSMCs can exist as one of two phenotypes: contractile or synthetic. Contractile VSMCs maintain vessel diameter through dilation or contraction, and thereby regulate blood flow. In response to damage, VSMCs can begin to proliferate and migrate to the site of damage, adopting the synthetic phenotype, which aids in vessel repair and remodeling.

However, proliferation and migration of VSMCs can be detrimental following intervention surgery. In these cases, VSMCs respond to vessel injury and the corresponding inflammatory environment by migrating to the site, proliferating, and releasing extracellular matrix proteins. This in turn, can cause vessel thickening, known as intimal hyperplasia, which is a significant risk factor and cause of vascular intervention failure. In addition, vascular smooth muscle cells can be the culprits of vascular calcification initiation, which is characterized by the deposition of calcium phosphate in vessels. The studies below investigate the roles of VSMCs in these processes.

Recent Studies Using Lifeline® Vascular Smooth Muscle Cells to Study Intimal Hyperplasia and Vascular Calcification

Endovascular intervention is a common treatment for peripheral vascular disease. However, although initial success is common, restenosis and initimal hyperplasia are associated with reintervention. Intimal hyperplasia results from vascular smooth muscle cell dysfunction, whereby smooth muscle cells undergo aberrant proliferation and migration. Attempts to target this cell population with siRNA to prevent intimal hyperplasia have been hindered by drug delivery challenges. Therefore, in a study from this year, Fisher et al. set out to develop nanoscale drug delivery vehicles using neutral liposomes, which have low toxicity, longer half lives, and are easily taken up by recipient cells. The authors compared the characteristics of three liposome types: (1) cationic liposomes (CLPs); (2) PEGylated liposomes (PLPs); and (3) R8-modified PLPs (PLPs coated with R8, a cell-penetrating peptide that facilitates translocation across recipient cell membranes).

The authors first found that R8-modified PLPs had similar siRNA encapsulating abilities as CLPs. They next determined that R8-PLPs significantly associated with Lifeline® human aortic smooth muscle cells at a 10%mol concentration. Although this cellular association was not as great as that observed with CLPs, R8-PLPs displayed significantly less cytotoxicity than CLPs, which is a crucial characteristic for drug delivery vehicles. Importantly, only R8-modified PLPs carrying siRNA against GAPDH could induce significant GAPDH silencing. Therefore, although more research needs to be done (including in vivo studies), the findings from this study demonstrate that cell-penetrating peptide-modified PLPs have therapeutic promise as carriers for siRNAs to direct gene therapy for initimal hyperplasia.

Vascular calcification occurs when minerals accumulate in the vessels, which can lead to cardiovascular complications. Importantly, dialysis patients often experience vascular calcification, which is attributed to inflammation that occurs due to unsatisfactory filtration of inflammatory chemokines and cytokines during dialysis. More stringent dialysis membranes have been developed to address this problem, and are categorized into high-cutoff and medium-cutoff membranes. Dialysis membrane development is challenging, as it is important to filter out inflammatory molecules without compromising the levels of important homeostatic molecules, such as albumin.

In a study from this year, Willy et al. used an in vitro dialysis system to investigate the effects of very permeable high-flux (HF) membranes, as well as less permeable HCO and MCO membranes on eliminating inflammatory interleukin (IL)-6, as well as calcification-inducing factors. They developed an in vitro dialysis system in which healthy donor plasma or LSP-activated donor plasma was dialyzed with each of the three membrane types. The different sera were then added to Lifeline® human vascular smooth muscle cells grown in VascuLife® medium to evaluate the effects of each dialysis method.

The authors first established that IL-6 levels were more efficiently eliminated from LPS-activated plasma using HCO and MCO membranes. Next, they found that although HF-dialyzed LPS-activated plasma caused a small decrease in smooth muscle cell calcification compared to undialyzed LPS-activated plasma, dialysis with HCO and MCO membranes significantly lowered calcification to the level of healthy plasma. Finally, the authors examined the levels of matrix Gla protein and osteopontin, two proteins involved in calcification, in the supernatant of vascular smooth muscle cells incubated with each sera type. They found that high-flux membranes decreased the levels of both proteins, but the most significant decrease occurred following HCO- and MCO-mediated dialysis. Together, the results of this study demonstrate that HCO and MCO dialyzers are superior to high-flux dialyzers for eliminating pro-inflammatory IL-6 and calcification-related proteins.

Lifeline® offers an extensive catalog of smooth muscle cells from various organ sites, optimized for growth in VascuLife® SMC medium, including:

Keep us updated! How are you using Lifeline® cells in your research? Have you developed any new assays? Share your research with us and if could be featured here on our blog!