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

• Published in: Journal of vascular surgery Vol. 52; no. 5; pp. 1310 - 1320
• Main Authors: Chen, Yih-Sharng, MD, PhD, Lu, Ming-Jen, MD, Huang, Ho-Shiang, MD, PhD, Ma, Ming-Chieh, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.11.2010; Elsevier
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Arginase - metabolism; Arteriovenous Shunt, Surgical; Benzylamines - administration & dosage; Biological and medical sciences; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Capsaicin - administration & dosage; Capsaicin - analogs & derivatives; Emergency and intensive care: renal failure. Dialysis management; Female; Femoral Artery - surgery; Femoral Vein - drug effects; Femoral Vein - metabolism; Femoral Vein - pathology; Femoral Vein - physiopathology; Femoral Vein - surgery; Hemodynamics; Iliac Vein - drug effects; Iliac Vein - metabolism; Iliac Vein - pathology; Iliac Vein - physiopathology; Iliac Vein - surgery; Infusion Pumps, Implantable; Infusions, Intravenous; Intensive care medicine; Ligation; Matrix Metalloproteinase 2 - metabolism; Mechanotransduction, Cellular - drug effects; Medical sciences; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Protein Kinase Inhibitors - administration & dosage; Rats; Rats, Wistar; RNA, Messenger - metabolism; Sensory System Agents - administration & dosage; Sulfonamides - administration & dosage; Surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Time Factors; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism; Vascular surgery: aorta, extremities, vena cava. Surgery of the lymphatic vessels; Vascular remodeling; Vertebrata; Mammalia; Rat; Animal; Surgery; Rodentia; Cardiovascular disease
• ISSN: 0741-5214; 1097-6809
• DOI: 10.1016/j.jvs.2010.05.095

Objective We 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. Methods The 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. Results The 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. Conclusion These 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.