Vascular remodeling in arteriovenous fistula treated with PDE5A inhibitors

Abstract

The arteriovenous fistula (AVF) is the lifeline for hemodialysis patients. However, there are currently no effective therapies promoting AVF maturation. AVF dilation by smooth muscle cell relaxation, through increased cyclic guanosine monophosphate (cGMP), is one potential mechanism to improve AVF remodeling. In this study, we examined the cGMP pathway and its inhibitor phosphodiesterase 5A (PDE5A) in rat, pig, and human AVF. We administered the PDE5A inhibitor, sildenafil, to rats with femoral AVFs and analyzed AVF histological and hemodynamic parameters. We observed that AVF creation increases PDE5A expression in rodent and porcine AVF models. Similarly, we observed an increase in PDE5A expression in the anastomotic regions of AVFs from hemodialysis patients when compared to pre-AVF placement. Sildenafil-treated rats showed significantly increased ultrasound-derived AVF volumetric blood flow and increased MRI-derived 3-dimensional lumen diameter when compared to controls. MRI-based computational fluid dynamics showed that sildenafil-treated rats had increased anastomotic hemodynamics compared to control rats. Histology showed similar intimal hyperplasia in sildenafil-treated and control rats. In conclusion, sildenafil treatment increases AVF vein outward expansion and blood flow without affecting the level of intimal hyperplasia. PDE5A inhibitors serve as a potential therapeutic approach to promote AVF maturation by enhancing outward vascular remodeling.

Keywords: PDE5A; arteriovenous fistula; hemodialysis; sildenafil; vascular access; vascular remodeling.

FIGURE 1

PDE5A expression after AVF creation surgery in rats. (a) Representative immunofluorescence of PDE5A, smooth muscle actin (α‐SMA), and DAPI in contralateral control veins and AVF veins 7 days after AVF creation surgery. Boxed images are at 40x magnification. (b) Representative western blot and densitometric analysis (n = 4/group).

FIGURE 2

PDE5A expression after AVF creation surgery in pigs. Representative immunofluorescence staining of PDE5A, smooth muscle actin (α‐SMA), and DAPI in contralateral control veins and AVF veins 7 days after AVF surgery. Boxed images are at 40x magnification.

FIGURE 3

PDE5A expression in ESKD patient tissues before and after AVF surgery. Representative immunofluorescence staining of PDE5A, smooth muscle actin (α‐SMA), and DAPI from the vein prior to AVF creation surgery (1st stage) and at the AVF anastomotic region after AVF creation surgery (2nd stage).

FIGURE 4

Intimal hyperplasia in rats after sildenafil treatment. Left panels show representative images of Russell‐Movat pentachrome staining of control (left) and sildenafil (middle) treated rats. Right panel shows intimal hyperplasia quantification as the ratio of intima to media area from AVF veins of control and sildenafil treated rats 7 and 28 days after AVF surgery (N = 3‐6/group).

FIGURE 5

Ultrasound and volumetric flow of sildenafil‐treated rats. (a) Representative B mode Doppler color images and waveform of AVF vein and arteries from sildenafil and control treated rats. (b) Volumetric blood flow (mL/min) quantification of vein (left panel) and artery (right panel). N = 6 in each group. Exact p value is for AVF – No treatment vs. AVF – Sildenafil. p < 0.0001 for AVF – No treatment and AVF – Sildenafil compared to contralateral controls at Day 7 or Day 28. In this figure, “No treatment” refers to control‐treated rats.

FIGURE 6

Hemodynamics of rat AVF at 21 days after creation surgery. (a) Wall shear stress (WSS) and (b) vorticity color maps of longitudinal and radial slices at systole and diastole. The black line in the longitudinal slices show location of respective radial slices. (c) WSS and (d) vorticity over a cardiac cycle. Data in (c, d) extracted from radial slices in (a, b). Error bars show ± SD. Control was significantly different from sildenafil when averaged over the cardiac cycle (p < 0.001, n = 44 data points; 4 rats/group).