Lactate Promotes Synthetic Phenotype in Vascular Smooth Muscle Cells

Abstract

Rationale The phenotypes of vascular smooth-muscle cells (vSMCs) comprise a continuum bounded by predominantly contractile and synthetic cells. Some evidence suggests that contractile vSMCs can assume a more synthetic phenotype in response to ischemic injury, but the mechanisms that activate this phenotypic switch are poorly understood. Objective To determine whether lactate, which increases in response to regional ischemia, may promote the synthetic phenotype in vSMCs. Methods and Results Experiments were performed with vSMCs that had been differentiated from human induced pluripotent stem cells and then cultured in glucose-free, lactate-enriched (L+) medium or in standard (L−) medium. Compared to the L− medium, the L+ medium was associated with significant increases in synthetic vSMC marker expression, proliferation, and migration, and with significant declines in contractile and apoptotic activity. Furthermore, these changes were accompanied by increases in the expression of monocarboxylic acid transporters (MCT) and were generally attenuated both by the blockade of MCT activity and by transfection with iRNA for N-myc downstream regulated gene (NDRG). Proteomics, biomarker, and pathway analyses suggested that the L+ medium tended to upregulate the expression of synthetic vSMC markers, the production of extracellular proteins that participate in tissue construction or repair, and the activity of pathways that regulate cell proliferation and migration. Observations in hypoxia-cultured vSMCs were similar to those in L+ cultured vSMCs, and assessments in a swine myocardial infarction model suggested that measurements of lactate levels, lactate dehydrogenase levels, vSMC proliferation, and MCT and NDRG expression were greater in the ischemic zone than in nonischemic tissues. Conclusions These results demonstrate for the first time that vSMCs assume a more synthetic phenotype in a microenvironment that is rich in lactate. Thus, mechanisms that link glucose metabolism to vSMC phenotypic switching could play a role in the pathogenesis and treatment of cardiovascular disease.

Smooth muscle glucose metabolism promotes monocyte recruitment and atherosclerosis in a mouse model of metabolic syndrome

“…Because lactate has recently been shown to promote a phenotypic switch in SMCs differentiated from human induced pluripotent stem cells (a switch that was dependent on expression of the monocarboxylic acid transporter MCT4 [Slc16a4]; ref. 38), we analyzed Slc16a4 mRNA levels in SMCs stimulated with TNF-α in the presence and absence of aldose reductase inhibitors. Aldose reductase inhibitors slightly suppressed Slc16a4 mRNA levels in the absence of TNF-α, and TNF-α stimulation resulted in an additional suppression, which was not affected by aldose reductase inhibitors ( Figure 7H).…”

Advanced glycation end products accelerate calcification in VSMCs through HIF-1α/PDK4 activation and suppress glucose metabolism

“…During injury and atherogenesis, VSMCs will transdifferentiate from a contractile to a synthetic phenotype 47 . Lactate, the end product of glycolysis, has been reported to have an important role in promoting the synthetic phenotype in VSMCs 48 . Lactate can also induce osteoblast differentiation via HIF-1α 49 , and these findings demonstrate that enhanced glycolysis is important for VSMC phenotype differentiation and vascular function changes.…”

TNF-α elicits phenotypic and functional alterations of vascular smooth muscle cells by miR-155-5p–dependent down-regulation of cGMP-dependent kinase 1

“…miR-155-5p levels were analyzed by the miScript primer assay with miR-155-5p-specific and universal primers and normalized to SNORD-95. Total mRNAs were also isolated from cells or tissues using TRIzol reagent, and the mRNA levels of target genes were determined and quantitated by qRT-PCR using their specific primers and normalized to glyceraldehyde-3-phosphate dehydrogenase (48). The primers used in this study are presented in Table S1.…”