The role of PRH/HHEX in the modulation of endothelial cell and intimal hyperplasia: implications of vein graft disease

Abstract

Patients with complex coronary artery disease undergo bypass grafting surgery, with the saphenous vein (SV) as the most frequently used conduit. Unfortunately, SV grafts are susceptible to intimal hyperplasia (IH) and vein graft failure (VGF), resulting in low patency rates within 10 years following surgery. Endothelial cell (EC) injury and dysfunction, results in abnormal communication with vascular smooth muscle cells (VSMCs) and contributes to phenotypic switching characterised by aberrant proliferation and migration of VSMC towards the subendothelial space, and resultant IH. Due to frequent use and poor patency of SV grafts the development of new therapies is necessary to reduce VGF.
Proline-rich homeodomain/haematopoietically expressed homeobox (PRH/HHEX) is a master transcriptional regulator of cellular proliferation and growth. Previous studies demonstrated that adenovirus-mediated overexpression of a stable mutant form of PRH/HHEX (RAd:PRH-CC) reduced VSMC proliferation and migration, without detrimental effects on ECs. Here, the porcine arteriovenous interposition graft model was utilised to characterise graft remodelling in SV grafts and determine the association with PRH/HHEX protein expression over time. High levels of PRH/HHEX protein were observed in the endothelium of prepared SV but was diminished within a week of grafting and recovered by 12 weeks. A similar pattern of PRH/HHEX protein expression was observed in VSMCs and correlated with contractile phenotype markers. Subjecting ECs to venous or arterial fluid shear stress (FSS) in vitro, revealed that PRH/HHEX protein, but not mRNA, was reduced in ECs exposed to arterial FSS due to proteasomal activity. Lastly, overexpression of PRH/HHEX maintained EC phenotype and junctional integrity in static culture in vitro.
To conclude, reduced amounts of PRH/HHEX protein in ECs and VSMCs may contribute to VGF. PRH/HHEX overexpression in SV may therefore be beneficial to maintain the venous EC phenotype, inhibit aberrant VSMC proliferation and suppress IH and VGF.

Date of Award	4 Feb 2025
Original language	English
Awarding Institution	University of Bristol
Supervisor	Sarah J George (Supervisor), Jason L Johnson (Supervisor) & Thomas W Johnson (Supervisor)