Ludovic Melly

Therapeutic angiogenesis aims at promoting the growth of blood vessels to restore perfusion in ischemic tissues or aid tissue regeneration. Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis in development, repair, and disease. However, exploiting VEGF for therapeutic purposes has been challenging and needs to take into account some key aspects of VEGF biology. In particular, the spatial localization of angiogenic signals within the extracellular matrix is crucial for physiological assembly and function of new blood vessels. Fibrin is the provisional matrix that is universally deposited immediately after injury and supports the initial steps of tissue regeneration. It provides therefore several ideal features as a substrate to promote therapeutic vascularization, especially through its ability to present growth factors in their physiological matrix-bound state and to modulate their availability for signaling. Here, we provide an overview of fibrin uses as a tissue-engineering scaffold material and as a tunable platform to finely control dose and duration of delivery of recombinant factors in therapeutic angiogenesis. However, in some cases, fibrin has also been associated with undesirable outcomes, namely the promotion of fibrosis and scar formation that actually prevent physiological tissue regeneration. Understanding the mechanisms that tip the balance between the pro- and anti-regenerative functions of fibrin will be the key to fully exploit its therapeutic potential.

Therapeutic angiogenesis is the delivery of factors to promote vascular growth and holds promise for the treatment of ischemic heart conditions. Recombinant proteindelivery to the myocardium by factor‐decorated fibrin matricesis anattractive approach, thanks to the abilityto precisely control both dose and duration of the treatment, the use of a clinically approved material like fibrin and the avoidance of genetic modification. Here we investigated the feasibility of inducing therapeutic angiogenesis in the rat myocardium by a state‐of‐the‐art fibrin‐based delivery platform that we previously optimized. Engineered versions of murine VEGF₁₆₄and PDGF‐BB were fused with an octapeptide substrate of the transglutaminase coagulation factor fXIIIa (TG) to allow their covalent cross‐linking into fibrin hydrogels and release by enzymatic cleavage. Hydrogelscontaining either 100 μg/ml TG‐VEGF alone or in combination with 10 μg/ml TG‐PDGF‐BB or no factor were injected into rat myocardium. Surprisingly, vascular density was severely reduced in all conditions, both in and around the injection site, where large fibrotic scars were formed. Scar formation was not due to the presence of growth factors, adaptive immunity to human proteins, damage from injection, nor to mechanical trauma from the hydrogel stiffness or volume. Rather scar was induced directly by fibrin and persisted despite hydrogel degradation within 1 week. These results caution against the suitability of fibrin‐basedplatforms for myocardial growth factor delivery, despite their efficacy in other tissues, like skeletal muscle. The underlying molecular mechanisms must be further investigated in order to identify rational targets to prevent this serious side‐effect.

Robotic beating-heart totally endoscopic coronary artery bypass

Vascular Endothelial Growth Factor (VEGF) can induce normal or aberrant angiogenesis depending on the amount secreted in the microenvironment around each cell. Towards a possible clinical translation, we developed a Fluorescence Activated Cell Sorting (FACS)‐based technique to rapidly purify transduced progenitors that homogeneously express a desired specific VEGF level from heterogeneous primary populations. Here, we sought to induce safe and functional angiogenesis in ischaemic myocardium by cell‐based expression of controlled VEGF levels. Human adipose stromal cells (ASC) were transduced with retroviral vectors and FACS purified to generate two populations producing similar total VEGF doses, but with different distributions: one with cells homogeneously producing a specific VEGF level (SPEC), and one with cells heterogeneously producing widespread VEGF levels (ALL), but with an average similar to that of the SPEC population. A total of 70 nude rats underwent myocardial infarction by coronary artery ligation and 2 weeks later VEGF‐expressing or control cells, or saline were injected at the infarction border. Four weeks later, ventricular ejection fraction was significantly worsened with all treatments except for SPEC cells. Further, only SPEC cells significantly increased the density of homogeneously normal and mature microvascular networks. This was accompanied by a positive remodelling effect, with significantly reduced fibrosis in the infarcted area. We conclude that controlled homogeneous VEGF delivery by FACS‐purified transduced ASC is a promising strategy to achieve safe and functional angiogenesis in myocardial ischaemia.

Osteogenesis imperfecta is a genetic disorder of connective tissue causing mostly left-sided heart valves and aortic root pathologies, but a coronary artery involvement reflecting an increased sensitivity to cardiovascular risk factors is also suspected in this patient population. We report a 38-year-old patient with an osteogenesis imperfecta and a typical presentation of an acute myocardial infarction. The coronary angiogram showed a coronary 3-vessel disease. The patient underwent a bypass grafting surgery with the internal mammary artery. The sternum was closed using four nitinol clips and had totally stabilized at 4 months with excellent bone healing. With the successful clinical outcome in this patient severely affected by its osteogensis imperfecta, we underline the safe use of the LIMA, if precaution is taken towards the sternal bone, and its closure with nitinol clips.