fig3

Figure 3. Mechanisms linking increased venous hydrostatic pressure to upregulation of MMPs in varicose veins. Increased lower extremity venous hydrostatic pressure causes vein wall stretch, increased HIF mRNA expression and protein levels, and increased MMP levels. Increased vein wall stretch could also increase other MMP inducers such as EMMPRIN, chymase, hormones and NGAL. Increased MMPs may activate PARs in endothelial cells leading to activation of NO-cGMP pathway or EDHF and BK_Ca channels in VSM, leading to hyperpolarization, decreased Ca²⁺ influx, and VSM relaxation. Prolonged loss of contractile function in VSM causes a phenotypic switch to synthetic VSMCs and increased propensity to stretch. MMPs may also increase the release of growth factors and cause ECM degradation leading to VSMC migration, further decreases in vein contraction and increases in venous dilation, and VVs. MMP-induced ECM degradation may also cause valve degeneration leading to further increases in venous hydrostatic pressure. As indicated in shaded arrows, inhibitors of MMP synthesis (U-0126, HIF siRNA, 17-DMAG, Echinomycin, MMP siRNA), activity (MMP inhibitor) or actions (Iberiotoxin) represent potential new tools for management of VVs. BK_Ca: Large conductance Ca²⁺-activated K⁺ channels; DMOG: dimethyloxallyl glycine, inhibitor of HIF-prolyl hydroxylase; HIF: hypoxia-inducible factor; Hsp90: heat shock protein 90. MAPK: mitogen-activated protein kinase. SMCs: smooth muscle cells; siRNA: small interfering RNA; MMP: matrix metalloproteinase; EMMPRIN: extracellular matrix metalloproteinase inducer; NGAL: neutrophil gelatinase-associated lipocalin; PARs: protease activated receptors; VSM: vascular smooth muscle; ECM: extracellular matrix; VSMCs: VSM cells; VVs: varicose veins.