Director D. Henrion
CARdiovascular MEchanotransduction (CARME) Scientific Program
Resistance arteries mechanotransduction in ischemic disorders and cardioprotection.
Resistance arteries, the small blood vessels located upstream capillaries, are crucial to the delivery of blood to vital tissues at relevant flow and pressure (1). Disorders of these small arteries can raise capillary pressure and cause downstream organ damage such as that seen in diabetes (2), neurovascular disorders (3) or kidney disease (4). The general objective of our project is to define how structure and function of small arteries change in ischemic disorders associated with ageing and the related risk factors. The project will identify during healthy and diseased ageing, the specific changes in pathways involved in resistance artery homeostasis leading to the identification of novel targets/biomarkers for intervention and disease prevention. Ageing enhances the probability of cardiovascular and metabolic diseases especially in countries where life expectancy increases together with exposure to environmental risks factors. Whereas the impact of healthy and diseased ageing on large arteries is well recognized (5), their impact on resistance arteries is less characterized. Nevertheless, they are progressively altered with age, due to inappropriate changes in resistance arteries structure and function (2). Indeed, human resistance arteries structure has a strong and independent prognostic significance in hypertensive and diabetic patients (1, 6). Although resistance arteries efficacy decreases with age, this is without major consequence in healthy ageing. Nevertheless, resistance arteries structure and function are further deteriorated by risk factor(s) so that a critical point is reached earlier in time leading to serious damages. Resistance arteries determine vascular resistance through their passive properties (diameter, thickness) and active tone. They possess a basal tone resulting of the interaction between pressure-induced contraction and flow-mediated dilatation (FMD) due to endothelial cells stimulation by shear stress. Although endothelial dysfunction is correlated with an increased risk of vascular events (7, 8), the mechanism(s) of FMD remains insufficiently understood in resistance arteries (9).
We have 3 specific objectives:
Our first objective is to further investigate FMD in resistance arteries in order to better define the pathways involved with a special focus on the mechanosensitive channels and on the mechanosensitive receptors.
Chronic changes in blood flow induce vascular remodelling in order to normalize shear stress. Inward remodelling occurs after arterial occlusion and blood flow reduction (myocardial infarction or hindlimb ischemia) whereas outward remodelling allows collateral arteries growth in order to revascularize ischemic tissues.
Our second objective is thus to determine in resistance arteries the mechanism of inward remodelling involved in ischemic disorders and the mechanism of outward remodelling aiming at restoring tissue perfusion.
Finally, changes in tissue perfusion due to alteration in vascular tone and remodelling induce tissue ischemia-reperfusion injury such as that seen in limb ischemia, acute coronary syndromes, systemic haemodynamic impairment such as cardiogenic, septic shock and extracorporeal circulation. Impaired tissue perfusion inducing ischemia, and paradoxically the reperfusion process itself, induce irreversible cell damage, referred to as tissue ischemia-reperfusion injury. Despite numerous improvements that have been made in management strategies for at-risk patients to reduce ischemia-related tissue damage, limiting injury remains a major challenge.
Our third objective is thus to investigate the mechanisms involved in ischemia-reperfusion injury and to bring forward new strategies to prevent its occurrence.
We currently investigate the short term regulation of local blood flow (autoregulation) and its long-term regulation (remodelling) using in vivo and in vitro mouse model as well as human blood vessels collected from patients suffering ischemic disorders and healthy subjects. Practically, flow-dependent mechanotransduction is be investigated using in vitro arteriography for isolated arteries (more details in the description of the CARFI facility) and vascular cells submitted to flow shear stress. We actually focus on mechanosentive receptors (GPCRs) and vascular sodium channels (Nav). The chronic response to flow (remodelling) is investigated using human biopsies and in vivo mouse models.
Finally, ischemic disorders are investigated using mouse models of ischemia/reperfusion in healthy and diseased ageing and in human vessels from patients with severe limb ischemia and healthy volunteers.
1. Heagerty AM, Heerkens EH, and Izzard AS. Small artery structure and function in hypertension. J Cell Mol Med 14: 1037-1043, 2010.
2. Levy BI, Schiffrin EL, Mourad JJ, Agostini D, Vicaut E, Safar ME, and Struijker-Boudier HA. Impaired tissue perfusion: a pathology common to hypertension, obesity, and diabetes mellitus. Circulation 118: 968-976, 2008.
3. Dunn KM and Nelson MT. Neurovascular signaling in the brain and the pathological consequences of hypertension. Am. J. Physiol. Heart and circulatory physiology 306: H1-14, 2014.
4. Patel A and Honore E. Polycystins and renovascular mechanosensory transduction. Na. Rev Nephrol 6: 530-538, 2010.
5. Lahoute C, Herbin O, Mallat Z, and Tedgui A. Adaptive immunity in atherosclerosis: mechanisms and future therapeutic targets. Nat Rev Cardiol 8: 348-358, 2011.
6. Rizzoni D and Agabiti-Rosei E. Structural abnormalities of small resistance arteries in essential hypertension. Intern Emerg Med 7: 205-212, 2012.
7. Struijker-Boudier HA, Rosei AE, Bruneval P, Camici PG, Christ F, Henrion D, Levy BI, Pries A, and Vanoverschelde JL. Evaluation of the microcirculation in hypertension and cardiovascular disease. Eur Heart J 28: 2834-2840, 2007.
8. Poredos P and Jezovnik MK. Testing endothelial function and its clinical relevance. J Atheroscler Thromb 20: 1-8, 2013.
9. Stoner L, Erickson ML, Young JM, Fryer S, Sabatier MJ, Faulkner J, Lambrick DM, and McCully KK. There's more to flow-mediated dilation than nitric oxide. J Atheroscler Thromb 19: 589-600, 2012.
- Pr. JF Arnal and Dr. F. Lenfant, INSERM 1048, Toulouse, Biology of ERa and mouse models.
- Dr. E. Honoré, IPMC, CNRS, Sophia-Antipolis, mechanosensitive channels and flow-sensing.
- Pr. A. Patapoutian, Scripps Research Institute, La Jolla, CA, USA, Study of Piezo1&2 channels.
- Pr. F. LeNoble, Kalsruhe Institut of Technology, Dl4-Notch pathway in flow-sensing.
- Pr. Z. Mallat, Dept of Medicine, University of Cambridge, UK, Pressure/flow interaction in arterial diseases.
- Pr.O. Lesaux, Hawai University, Hawai, USA, abcc6 pathophysiology.
- H. Castel, INSERM U982 and I. Milazzo, UMR CNRS 6014, Rouen, GPCRs Biocomputing.
- H. Abdi, University of Texas at Dallas, USA, GPCRs modeling.
- Pr. John Wood (UCL, UK), Nav chanels pathophysiology.
- Dr O. Blancbrude, PARCC-INSERM, HEGP, Paris, Circulating factors and vascular remodeling.
- Pr. G. Osol, Dept of Gyneco-obstetrics, University of Vermont, USA, Estrogens and vascular remodeling.
- Dr F. Pinet (INSERM U 1167, institute Pasteur, Lille), molecular analysis of cardiac disorders.
- Pr. T. Huet (INSERM U 1082, Poitiers), animal models of kidney disease
- Pr. M. Ovize (Team 5, INSERM U1060, Lyon), cardiac bioenergetics.
- INSERM RIRE (Réseau Infarctus de REperfusion) network: Angers (Pr. F. Prunier) Brest (Pr. M. Gillard), Lyon (Pr. M. Ovize), Montpellier (Pr. F. Roubille), Strasbourg (Pr. O. Morel), Toulouse (Pr. M. Elbaz), Tours (Pr. D. Angoulvant).