Vascular stiffness

The paradigm of arterial stiffness has recently shifted (1) from elastin/collagen content to vascular smooth muscle cell (VSMCs) tone as key molecular/cellular determinants of arterial wall stiffness; (2) from shear stress to tensile pulsatile circumferential stress, as key mechanical determinants of arterial wall remodeling; (3) and from abnormal microcirculation to large/small arteries cross-talk, as key determinants of target organ (brain, heart and kidney) damage in disease. Our previous findings highlighted the major role of VSMC plasticity in arterial stiffening and processes of early vascular ageing (EVA).

This research axis aims to delineate the mechanisms by which intramural cells sense and regulate the interaction of the cell with the extracellular matrix that endows arteries with much of their mechanical functionality and structural integrity, and the complex interactions amongst differently sized vessels.

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Coagulation – Vasculature coupling

Akin to arterial stiffness and pulse pressure, a prothrombotic state also increases consistently with age. Our previous results provided a first demonstration of a link between arterial stiffness and coagulation in aged patients. Although the mechanisms involved are still largely unclear, our data indicate a likely involvement of integrins. Since anti-platelet drugs and anticoagulants are in clinical use for atherothrombosis prevention, a better molecular understanding of the interplay between arterial stiffness and hypercoagulability has the potential to identify new pathophysiological mechanisms than can be targeted to inhibit early vascular aging.

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Specialized pro-resolving lipid mediators and calcifications

Lipid mediators are key orchestrators of cardiovascular inflammation during ageing. Pro-inflammatory leukotrienes contribute to atherosclerosis and cardiovascular calcification. In contrast, other lipid mediators oppose the actions of leukotrienes and act as the stop-signals needed for the resolution of inflammation. Such signaling molecules are termed specialized proresolving mediators (SPMs) and stimulate for example leukocyte egress from sites of inflammation and the uptake of apoptotic cells (efferocytosis). In contrast to acute inflammation, the chronic inflammation associated with ageing may result from a failure in the resolution of inflammation. 

Our research projects address several different aspects of lipid mediators of inflammation and resolution in cardiovascular ageing, with focus on vascular stiffness, vascular calcification, atherosclerosis and valvular heart disease.

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TREM-1 – platelets – endothelium – cardio-metabolic syndrome

TREM-1 stimulates the production of cytokines and pro-inflammatory chemokines by neutrophils and monocytes/macrophages. Over the past decade, we have discovered the key role of TREM-1 activation in sepsis and myocardial infarction and demonstrated the therapeutic potential of TREM-1 blockade to decrease inflammation and improve survival. We are continuing this successful line of research to elucidate the role of TREM-1 in thrombosis and endothelial dysfunction. We are also studying the involvement of TREM-1 in chronic heart failure.

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Acute heart failure and cardiovascular shock

The project is centered on bridge-to-recovery strategies leading to protect the integrity of heart and vessels, with a special emphasize on the adrenergic system, considered alone or in association with assistance techniques. Cardiovascular protection may be partly achieved through adrenergic inhibition and we demonstrated that β1 adrenergic inhibition with esmolol may be beneficial in septic shock. This leads to immune-modulatory effects presumably because β1-blockade also acts on immune cells. In experimental septic choc, we expect to determine whether the depletion in β1-adrenoceptors or their inhibition (non-chronotropic doses of esmolol) influence the infiltration of monocyte/macrophages into heart and vessels and also, enhance the differentiation from Th0 into the Th2 non-inflammatory cells. Additionally, by using the β1/β2-adrenoceptor double knock out, we expect to better understand the synergic effect of β1 and β2-adrenoceptors.

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Telomere dynamics and vascular aging

The progressive life-long aging of the cardiovascular system is markedly involved in the high rates of diseases. Our studies have contributed to establish: (i) the association between short leucocyte telomere length (TL) and several age-related arterial diseases and (ii) that TL is mainly determined before adulthood. Telomeres ranking (having short or long TL) is stable during adult life and is thus likely to be established before the first clinical manifestations of atherosclerosis, leading to wonder whether short TL is mechanistically related to the subsequent development of aging-related diseases.

Our project involves both cross-sectional and longitudinal studies, in order to provide information from different elements of TL dynamics (TL at birth, early and late life attrition) and significant knowledge about the relationship between cardiovascular aging and TL.

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Personalized strategies to prevent, monitor and treat chronic HF

The project is focused on selected mechanisms relevant to the development of chronic heart failure, with an emphasis of the role of kidney dysfunction, mineralocorticoid receptors (MR), inflammation and hemodynamic factors. The aim is to identify and validate blood-systemic and imaging-focal new biomarkers to develop a new classification of chronic heart failure. This will open up new strategies of disease management taking into account relevant co-morbidities (especially chronic kidney disease, hypertension and obesity) and biomarkers in a “multidimensional” approach mixing omics research and imaging technologies.

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