Mechanosensitive transient receptor potential vanilloid type 1 channels contribute to vascular remodeling of rat fistula veins.
Summary of "Mechanosensitive transient receptor potential vanilloid type 1 channels contribute to vascular remodeling of rat fistula veins."
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 Ca(2+)-permeable TRPVs play a role in remodeling of fistula veins.
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.
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 Ca(2+)/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.
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.
Department of Cardiovascular Surgery, National Taiwan University Hospital, Taipei, Taipei, Taiwan.
This article was published in the following journal.
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20638226
- DOI: http://dx.doi.org/10.1016/j.jvs.2010.05.095
Medical and Biotech [MESH] Definitions
Transient Receptor Potential Channels
A broad group of eukaryotic six-transmembrane cation channels that are classified by sequence homology because their functional involvement with SENSATION is varied. They have only weak voltage sensitivity and ion selectivity. They are named after a DROSOPHILA mutant that displayed transient receptor potentials in response to light. A 25-amino-acid motif containing a TRP box (EWKFAR) just C-terminal to S6 is found in TRPC, TRPV and TRPM subgroups. ANKYRIN repeats are found in TRPC, TRPV & TRPN subgroups. Some are functionally associated with TYROSINE KINASE or TYPE C PHOSPHOLIPASES.
Trpv Cation Channels
A subgroup of TRP cation channels named after vanilloid receptor. They are very sensitive to TEMPERATURE and hot spicy food and CAPSAICIN. They have the TRP domain and ANKYRIN repeats. Selectivity for CALCIUM over SODIUM ranges from 3 to 100 fold.
Calcium Channels, T-type
A heterogenous group of transient or low voltage activated type CALCIUM CHANNELS. They are found in cardiac myocyte membranes, the sinoatrial node, Purkinje cells of the heart and the central nervous system.
Potassium Channels, Voltage-gated
Potassium channel whose permeability to ions is extremely sensitive to the transmembrane potential difference. The opening of these channels is induced by the membrane depolarization of the ACTION POTENTIAL.
Receptor, Igf Type 2
A receptor that is specific for IGF-II and mannose-6-phosphate. The receptor is a 250-kDa single chain polypeptide which is unrelated in structure to the type 1 IGF receptor (RECEPTOR, IGF TYPE 1) and does not have a tyrosine kinase domain.
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