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Raffetto et al. Vessel Plus 2021;5:36 https://dx.doi.org/10.20517/2574-1209.2021.16 Page 15 of 30

and Fas and their receptors. MMP-1, -2, - 8, -9, -13, -14 and -17 cleave the TNF-α precursor pro-TNF-α into
its active form [129,130] . Also, MMP-7 cleaves Fas-L leading to its shedding from the cell surface [131,132] . MMP-2
has been localized in the nucleus of isolated cardiac myocytes, where it promotes caspase-dependent
[133]
cleavage of the DNA repairing enzyme poly-ADP ribosepolymerase and leads to cell apoptosis . While
MMPs regulate cell apoptosis, the contribution of SMC apoptosis to VVs pathology needs to be further
examined.

Besides the tunica adventitia and ECM, the localization of MMPs in the tunica intima and tunica media
suggests additional effects on endothelial cells and VSMCs [58,59] . In rat mesenteric arteries, MMP-2 and -7
through PI K activation and ATP synthesis cause transactivation of epidermal growth factor receptor and
3
maintain phenylephrine-induced vascular tone. In support, MMP-2 or -7 knockdown by siRNA blunts Akt
[134]
phosphorylation of PI K in rat aortic VSMCs . On the other hand, MMP-2 and MMP-9 inhibit
3
phenylephrine-induced contraction in rat aortic segments in a time-dependent, concentration-dependent,
and reversible fashion, which suggests that the MMP effects are not caused by irreversible proteolysis and
degradation of ECM protein components . Also, the MMP-induced inhibition of the VSM contractile
[135]
response may not be due to destruction of the phenylephrine molecule or proteolytic degradation of the α-
adrenergic receptors because MMPs also inhibit vascular contraction induced by prostaglandin F2α, and
these observations can be interpreted as direct effects of MMPs on a common post-receptor VSMC
2+
contraction mechanism. VSMC contraction is initiated by Ca release from the sarcoplasmic reticulum and
2+
maintained by Ca influx through plasma membrane channels. Our previous studies have shown that
MMP-2 and MMP-9 do not affect phenylephrine-induced contraction in rat aortic segments incubated in
Ca -free solution, suggesting that MMPs do not affect the Ca release mechanism from the sarcoplasmic
2+
2+
[135]
reticulum . Importantly, MMP-2 and MMP-9 inhibit Ca influx in rat aortic segments , and MMP-2
2+
[135]
inhibits extracellular Ca -dependent contractile response in rat IVC . It could be argued that MMPs
2+
[136]
induce protein degradation and in turn produce Arg-Gly-Asp (RGD)-containing peptides, which could
bind to α β integrins and lead to inhibition of Ca influx into VSMCs . This may be unlikely because our
[137]
2+
v 3
experiments with RGD peptides showed that they did not inhibit the IVC contractile response . One
[136]
possibility is that MMPs could activate PARs and their downstream signaling pathways leading to blockade
of Ca channels in VSMCs . In support, thrombin acts as a protease and activates PARs, consequently
[138]
2+
2+
promoting endothelium-dependent inhibition of Ca influx and relaxation of VSMCs . We have
[139]
previously reported that the relaxation of rat IVC segments induced by MMP-2 is prevented in veins
incubated in a high KCl depolarizing solution, which blocks outward movement of K ion via
+
plasmalemmal K channels. Also, iberiotoxin, a blocker of large-conductance Ca -activated K channels
+
+
2+
(BK ), inhibited MMP-2 induced relaxation of rat IVC, which suggests that MMP-2 actions involve
Ca
membrane hyperpolarization, activation of BK , and inhibition of Ca entry through voltage-dependent
2+
Ca
2+
[140]
2+
Ca channels [Figure 3] . Long-term, maintained MMP-induced inhibition of Ca entry and the vein
contractile response could lead to progressive venous dilation and formation of VVs.
MMPs and endothelial integrity and function
VVs often show inflammatory cell infiltration and increased ICAM-1 and VCAM-1 expression [57,84,116] , and
these effects could be related to changes in MMP expression. MMPs regulate endothelial integrity and
vascular permeability. Application of supernatants from cultured colon cancer and melanoma cells on
human umbilical endothelial cells (HUVECs) and human dermal microvascular endothelial cells renders
the cells a more prothrombotic, proinflammatory, and cell-adhesive state through activation of MMP-
1/PAR-1 pathway . In mouse aorta, MMP-13 induced cleavage of ICAM-1 may require endothelial nitric
[141]
oxide synthase . Upregulation of MMP-2 and MMP-9 plays a role in the increases in vascular
[142]
[143]
permeability and membrane disruption induced by human immunodeficiency virus-1 in rat brain .
MMP-2 and MMP-9 also disrupt membrane barrier integrity in porcine brain capillary endothelial cells ,
[144]