Abstract 3597: Tool Drug Induced Activation Of Transient Receptor Potential Cation Channel, Subfamily V, Member 4 Triggers Collateral Growth After Femoral Artery Ligature In Pigs
Purpose: Peripheral artery disease (PAD) with chronic arterial occlusion leads to growth of collaterals - a process termed arteriogenesis. It was previously shown that fluid shear stress (FSS), which is also known to be an initial trigger of collateral growth, activates the transient receptor potential cation channel, subfamily V, member 4 (Trpv4). The aim of our study was to enhance collateral growth via Trpv4 activation in a pig hind limb ischemia model.
Methods: Domestic pigs (n=32, 40±1kg) were subjected to femoral artery ligature. 4α-Phorbol 12,13-didecanoate (4α-PDD, a Trpv4 activator) in different concentrations (9, 18, and 36 μg/kg/day) or 0.7 mg/kg/day Ruthenium Red (RR, a Trpv4-blocker) were infused into the femoral artery via an osmotic mini pump proximal to the ligature (n=26). NaCl-filled minipumps served as controls (n=6). Before, directly after ligature and on day 7 aortic and peripheral (A. saphena) mean arterial pressure (MAP) were measured, and angiographic images were obtained. Tissue was isolated from M. quadriceps for immunohistochemistry and from collateral arteries for quantitative real time PCR (qRT-PCR).
Results: Angiographic images showed enhanced collateral growth in 4α-PDD treated pigs compared to controls. Compared to aortic MAP, peripheral MAP increased from 30.8±4.3% (n=26) shortly after ligature to 62.0±7.5% in sham-treated pigs. Treatment with 4α-PDD revealed a significant dose-dependent increase of peripheral MAP with a maximal improvement to 80.0±3.3% compared to aortic MAP, (p<0.05, each n=5). qRT-PCR showed increased transcription of Abra, which was previously described as key regulator of arteriogenesis. Increased proliferative activity in collaterals could be shown by Ki67 staining. In contrast, the Trpv-blocker RR resulted in a reduction of peripheral MAP in comparison to controls (55.0±10.0%, n=5, vs. 62.0±7.5%, n=6).
Conclusion: The dose-dependent improvement of peripheral MAP after 4α-PDD treatment identifies Trpv4 as an initial sensor of FSS and a trigger for collateral remodelling and growth. The relevant enhancement of peripheral pressure after Trpv4 activation compared to natural occurring processes of arteriogenesis might represent a new therapeutic strategy in treatment of PAD.