The role of mechanobiology in establishment and progression of intima hyperplasia associated to Vein coronary bypass Grafts Disease

People involved: Monica Soncini, Gianfranco B. Fiore, Marco Piola

Funding source: Italian Ministry of Health

Grant number: RF-2011-02346867

Funding period: November 2014 – November 2017

Partners: Dipartimento di Elettronica, Informazione e Bioingegneria - Politecnico di Milano; Laboratorio di Ingegneria Tissutale Cardiovascolare - Centro Cardiologico S.P.A. Fondazione Monzino; Laboratory of Diabetological Research – IRCCS MultiMedica

Coronary artery by-pass grafting (CABG) is a standard surgical procedure to re-vascularize the ischemic myocardium of patients with coronary artery disease. Autologous saphenous veins are commonly used for the coronary artery by-pass grafting even if they are liable to progressive patency reduction. The failure of vein grafts is due to a pathologic condition, named vein graft disease (VGD), caused by an over-proliferation of smooth muscle cells, which accumulate in the intimal layer, progressively narrow the lumen, and decrease its patency.

Recently, a role of mechanical stress as a 'primus movens' in intima hyperplasia has been hypothesised; in particular, changes in wall strain consequent to vein arterialization may be 'sensed' by vein resident cells as a vascular damage signal, leading to direct smooth muscle cells activation or paracrine activation of vessels-resident progenitor cells. This is relevant in the light of the recognition of the SV wall as a reservoir of progenitor cells endowed with multi-lineage differentiation ability, the so called "saphenous vein progenitors" (SVPs). The role of mechanical stress in VGD progression has remained underestimated until recent years. In fact, only with the introduction of ex vivo culture systems to perform cell or vessel mechanical conditioning, systematic studies addressing the role of mechanobiology in VGD have become feasible.

The objective of the present proposal is to understand the cellular and molecular basis of intima hyperplasia associated to VGD, using a yet un-attempted multidisciplinary approach focused on mechanobiology.

The results will be achieved by a multi-step research process:

1. investigating the effect of mechanical load on phenotype and function of human SVPs; equiaxial/uniaxial mechanical strain will be applied to SVPs and their SVPs response to mechanical load will be characterized by genome-wide transcriptional, epigenetic and secretome profiling;
2. developing a versatile platform to expose human vessels to venous perfusion or arterial-like pulsatile strain and biochemical features; morphometric and immunofluorescence, global gene expression, and DNA methylation studies will be performed on saphenous vein samples conditioned within the developed bioreactors;
3. identifying genes and recurrent epigenetic marks, which may be targeted by specific drugs and/or gene expression interfering strategies (e.g. siRNAs, antagoMIRs) with the aim of avoiding or limiting the VGD progression.