After completing this continuing education activity, you should be able to: ABSTRACT: Hypertrophic scars and keloids are firm, raised, erythematous plaques or nodules that manifest when the cicatrix fails to properly heal. They result from pathologic wound healing and often cause pain and decreased quality of life. The appearance of such cosmetically unappealing scars affects the confidence and self-esteem of many patients. These scars can also cause dysfunction by interfering with flexion and extension across joints. Both possess some unique and distinct histochemical and physiologic characteristics that set them apart morphologically and at the molecular level. While these entities have been the focus of research for many years, differentiating between them remains challenging for clinicians.This article reviews the clinical presentation of aberrant scars and illustrates how they can be differentiated. It outlines their pathophysiology and emphasizes the unique molecular mechanisms underlying each disorder. It also examines how altered expression levels and the distribution of several factors may contribute to their unique clinical characteristics and presentation. Further research is needed to elucidate optimal treatments and preventive measures for these types of aberrant scarring.

Arterial reconstruction procedures, including balloon angioplasty, stenting and coronary artery bypass, are used to restore blood flow in atherosclerotic arteries. Restenosis of these arteries has remained a major limitation of the application of these procedures, especially in the case of balloon angioplasty. Post-angioplasty restenosis results from two major processes: neointimal formation and constrictive remodelling. Neointimal formation is initiated by arterial injury with a resultant loss of contractile phenotype in tunica media, leading to VSMC [vascular SM (smooth muscle) cell] migration from the tunica media to the intima. Migrated VSMCs contribute to the intimal thickening by the excessive synthesis of ECM (extracellular matrix) and proliferation. However, increased neointimal mass is not solely responsible for luminal narrowing. Inward constrictive remodelling is also considered as a major cause of delayed failure of angioplasty. At later stages after angioplasty, the increase in contractile forces leads to lumen narrowing. Recent studies show that SM contractile proteins are re-expressed in the neointima, concomitant with late lumen loss. Therefore one important question is whether the restoration of contractile phenotype, which can suppress VSMC migration, is favourable or detrimental. In this review, the importance of viewing restenosis as a multistage process is discussed. Different stages of restenosis occur in a sequential manner and are related to each other, but in each stage a different strategy should be taken into consideration to reduce restenosis. Defining the role of each process not only reshapes the current concept, but also helps us to target restenosis with more efficacy.

OBJECTIVE The tonicity-responsive transcription factor, nuclear factor of activated T-cells 5 (NFAT5/TonEBP), has been well characterized in numerous cell types; however, NFAT5 function in vascular smooth muscle cells (SMCs) is unknown. Our main objective was to determine the role of NFAT5 regulation in SMCs. METHODS AND RESULTS We show that NFAT5 is regulated by hypertonicity in SMCs and is upregulated in atherosclerosis and neointimal hyperplasia. RNAi knockdown of NFAT5 inhibits basal expression of several SMC differentiation marker genes, including smooth muscle alpha actin (SMαA). Bioinformatic analysis of SMαA reveals seven putative NFAT5 binding sites in the first intron, and ChIP analysis shows NFAT5 enrichment of intronic DNA. Overexpression of NFAT5 increases SMαA promoter-intron activity, which requires an NFAT5 cis element at +1012, while dominant-negative NFAT5 decreases SMαA promoter-intron activity. Since it is unlikely that SMCs experience extreme changes in tonicity, we investigated other stimuli and uncovered two novel NFAT5-inducing factors: angiotensin II, a contractile agonist, and platelet-derived growth factor-BB (PDGF-BB), a potent mitogen in vascular injury. Angiotensin II stimulates NFAT5 translocation and activity, and NFAT5 knockdown inhibits an angiotensin II-mediated upregulation of SMαA mRNA. PDGF-BB increases NFAT5 protein and loss of NFAT5 inhibits PDGF-BB-induced SMC migration. CONCLUSIONS We have identified NFAT5 as a novel regulator of SMC phenotypic modulation and have uncovered the role of NFAT5 in angiotensin II-induced SMαA expression and PDGF-BB-stimulated SMC migration.

These data suggest that alpha 8 integrin expression is required for maintenance of the VSMC differentiated phenotype, a state that is crucial for non-motile VSMCs.

Our results are consistent with those of other studies demonstrating that alpha8 integrin could be used as an appropriate differentiation marker. In addition, depressed alpha8 integrin expression (after vascular injury or siRNA knockdown) was correlated with heightened cell migratory activity, demonstrating its potential role in neointima formation.

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Activation of vascular smooth muscle cells (VSMCs) to migrate and proliferate is essential for the formation of intimal hyperplasia. Hence, selectively targeting activated VSMCs is a potential strategy against vaso-occlusive disorders such as in-stent restenosis, vein-graft stenosis, and transplant vasculopathy. We show that CD98 heavy chain (CD98hc) is markedly up-regulated in neointimal and cultured VSMCs, and that activated but not quiescent VSMCs require CD98hc for survival. CD98hc mediates integrin signaling and localizes amino acid transporters to the plasma membrane. SMC-specific deletion of CD98hc did not affect normal vessel morphology, indicating that CD98hc was not required for the maintenance of resident quiescent VSMCs; however, CD98hc deletion reduced intimal hyperplasia after arterial injury. Ex vivo and in vitro, loss of CD98hc suppressed proliferation and induced apoptosis in VSMCs. Furthermore, reconstitution with CD98hc mutants showed that CD98hc interaction with integrins was necessary for the survival of VSMCs. These studies establish the importance of CD98hc in VSMC proliferation and survival. Furthermore, loss of CD98hc was selectively deleterious to activated VSMCs while sparing resident quiescent VSMCs, suggesting that activated VSMCs are physiologically dependent on CD98hc, and hence, CD98hc is a potential therapeutic target in vaso-occlusive disorders.

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