Abstract
BackgroundHyaluronan (HA) is a primary component of the extracellular matrix of cells, and it is involved in the pathogenesis of atherosclerosis. The purpose of this study was to investigate the role of HA in neointimal formation after vascular injury and determine its tissue-specific role in vascular smooth muscle cells (VSMCs) by using a cre-lox conditional transgenic (cTg) strategy.Methods and ResultsHA was found to be expressed in neointimal lesions in humans with atherosclerosis and after wire-mediated vascular injury in mice. Inhibition of HA synthesis using 4-methylumbelliferone markedly inhibited neointimal formation after injury. In vitro experiments revealed that low-molecular-weight HA (LMW-HA) induced VSMC activation, including migration, proliferation, and production of inflammatory cytokines, and reactive oxygen species (ROS). The migration and proliferation of VSMCs were mediated by the CD44/RhoA and CD44/ERK1/2 pathways, respectively. Because HA synthase 2 (HAS2) is predominantly expressed in injured arteries, we generated cTg mice that overexpress the murine HAS2 gene specifically in VSMCs (cHAS2/CreSM22α mice) and showed that HA overexpression markedly enhanced neointimal formation after cuff-mediated vascular injury. Further, HA-overexpressing VSMCs isolated from cHAS2/CreSM22α mice showed augmented migration, proliferation, and production of inflammatory cytokines and ROS.ConclusionVSMC-derived HA promotes neointimal formation after vascular injury, and HA may be a potential therapeutic target for cardiovascular disease.
Highlights
Neointimal formation after vascular injury is the pathological basis of the restenosis that occurs after revascularization procedures such as percutaneous coronary intervention (PCI)
The vascular smooth muscle cells (VSMCs) are the main factors involved in vascular wall remodeling after such injury, and it is currently accepted that neointimal formation after injury involves migration of medial VSMCs toward the lumen, where they proliferate and secrete extracellular matrix (ECM) proteins [1]
An accumulating body of evidence suggests that the interaction of ECM proteins with VSMCs plays a crucial role in the processes of neointimal formation after vascular injury [2], the underlying mechanisms are not completely understood
Summary
Neointimal formation after vascular injury is the pathological basis of the restenosis that occurs after revascularization procedures such as percutaneous coronary intervention (PCI). An accumulating body of evidence suggests that the interaction of ECM proteins with VSMCs plays a crucial role in the processes of neointimal formation after vascular injury [2], the underlying mechanisms are not completely understood. High-molecular-weight HA (HMW-HA .500 kDa) is the predominant isoform under physiological conditions It fragments during inflammation and tissue injury, and these HA fragments (i.e., low-molecular-weight HA [LMW-HA], ,500 kDa) exert angiogenic and proinflammatory effects. We examined the role played by HA in 2 types of vascular injury models in vivo and studied the effect of LMW-HA and HMW-HA on the migration and proliferation of VSMCs in vitro. The purpose of this study was to investigate the role of HA in neointimal formation after vascular injury and determine its tissue-specific role in vascular smooth muscle cells (VSMCs) by using a cre-lox conditional transgenic (cTg) strategy
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