Extracellular matrix analysis in vasculature in physiological and pathological conditions.

Endothelial dysfunction is one of the main triggers of atherosclerosis which is identified as a chronic inflammatory disease of the artery wall. The exact mechanisms underlying the impaired vascular structure and activity remain unresolved. Since inflammatory cytokine TNFα appears to be involved in the pathogenesis of atherosclerosis, we treated endothelial cells (HUVEC) with TNFα to see its influence on extracellular matrix components as hyaluronan (HA) and syndecans (SDCs). TNFα influence HA synthesis enzymes and its presence in the pericellular space. Moreover, it leads to syndecan4 (SDC4) core protein overexpression and alters its heparan sulfate (HS) chains. These mechanisms cause a reduction in HUVEC permeability, an upregulation of the critical enzymes involved in the synthesis of HS and an increase of N-sulfation of HS residues. This HS modifications could inhibit the thrombus formation decreasing the platelets spreading. These data suggest that, during endothelial inflammation, the alteration of HA synthesis, SDC4 expression and its GAGs chains chemical composition can influence the platelets recruitments and, further, could promote the LDL accumulation during the onset of atherosclerosis. Since the hepatic enzyme PCSK9 is a novel pharmacological target for patients with cardiovascular disease lowering the plasmatic concentration of LDL, we examined the action of PCSK9 on HA metabolism and LDL receptors in vascular cells. LDLR and LOX1, the main LDL receptors, are influenced by PCSK9. Moreover, PCSK9 affected HA synthesis enzyme expression. These data indicate that PCSK9 could have a vaso-protective role regulating molecules involved in HA homeostasis.