Mechanosensitive transient receptor potential vanilloid type 1 channels contribute to vascular remodeling of rat fistula veins

ObjectiveWe previously showed that matrix metalloproteinases (MMPs) contribute to tremendous blood flow-induced venous wall thickening during the maturation of an arteriovenous fistula (AVF). However, how veins in the fistula sense a dramatic change in the blood flow remains unknown. Because mechanosensitive transient receptor potential vanilloid channels (TRPVs) are present in the endothelium, we examined whether the Ca2+-permeable TRPVs play a role in remodeling of fistula veins.MethodsThe fistula veins were generated at femoral AVF of Wistar rats. Changes in the hemodynamics and the width and internal radius of the iliac vein were studied at 3, 7, 14, and 28 days, then the iliac vein was removed and examined for changes in wall thickness and protein or mRNA expression by immunofluorecent stain, Western blot, or real time PCR. Changes in MMP2 activity was examined by gelatin zymography. Two ligatures were performed in iliac vein to prevent venodilatation to confirm the effect of dramatic changes in hemodynamics on TRPV expression. The specific role of TRPV was studied in another group of fistula veins given with capsazepine via a subcutaneous mini-osmotic pump for 28 days.ResultsThe fistula veins demonstrated high flow/wall shear stress (WSS), wall thickening, and venodilatation compared with control veins. The WSS increase was positively correlated with upregulation of TRPV1, but not TRPV4. Narrowing fistula veins prevented TRPV1 upregulation, indicating that high flow directly upregulates TRPV1. We examined the underlying signaling components and found that enhanced Ca2+/calmodulin-dependent protein kinase II (CaMK II) activity upregulated endothelial nitric oxide synthase (eNOS) and downregulated arginase I in the fistula veins. These changes were reversed by a CaMK II inhibitor. The relative levels of eNOS and arginase I activity consequently augmented NO formation, which coincided with an increase in MMP2 activity. Chronic inhibition of TRPV1 in the fistula veins by capsazepine showed no effect on high flow and TRPV1 expression, but markedly attenuated WSS, which was concomitantly associated with attenuation of CaMK II activity, NO-dependent MMP2 activation, and remodeling.ConclusionThese findings indicate that TRPV1 is essential in the remodeling of AVFs and that WSS leads to TRPV1 upregulation, which then enhances remodeling, therefore, inhibition of TRPV1 pathway may prolong the lifespan of an AVF by decreasing WSS and vein wall remodeling.Clinical RelevanceThis study reveals that enhanced endothelial mechanosensation is requisite for the fistula remodeling in response to dramatic hemodynamic changes. Moreover, our findings demonstrate that Ca2+ signal triggered by TRPV1 upregulates eNOS and downregulates arginase I and which enhances NO formation to lead to MMP2 activation in extracellular matrix remodeling of fistula veins. These findings enhance understanding of the basic biologic mechanisms in the venous remodeling. The need for TRPV1-mediated remodeling suggests that clinical strategies to blunt mechanosensation of fistula veins during maturation might be more successful or prolong the life span of fistula veins if TRPV1 are inhibited as a part of the surgical or follow-up treatment