Abstract
Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease associated with exercise intolerance and cardiovascular comorbidities. These elements appear to be closely linked to the structure and function of muscle capillaries but also of upstream arteries. Although exercise training (ET) provide a beneficial effect on vascular function in healthy subjects, this effect appears to be blunt in COPD patients. The aim of this thesis work was thus to understand the impairments of the vascular adaptations to ET in COPD patients. In a first study, we analysed capillary ultrastructure during muscle angiogenesis in COPD patients and healthy sedentary control (HSC) subjects during an ET and demonstrated disturbances in pericyte/capillary interactions in patients. In a second study, we looked for abnormalities of pericyte coverage adaptations during ET-induced angiogenesis in COPD patients, as well as the effect of circulating factors on the determinants of pericyte coverage. We have thus shown a lack of pericyte coverage adaptation during ET-induced angiogenesis after 10 weeks of ET in COPD patients. In addition, we were able to observe that COPD patient’s serum disturbed pericyte recruitment in vitro. In a third study, we investigated the PGC1-α pathway expression and its proangiogenic effectors in the skeletal muscle stimulated with exercise, in patients with COPD and HSC. Through the isolation, differentiation and stimulation of muscle stem cells from muscles of COPD and HSC patients, we have demonstrated an impairment of the raise of PGC1-α expression under electrical pulse stimulation in muscle cells of COPD patients. A reduction in the production of SPP1 by these cells has also been found, limiting their ability to orchestrate capillary maturation. In a fourth study, we were interested in the clinical, functional, cellular and molecular determinants involved in the lack of response of arterial vasoreactivity to ET in COPD patients. To address these questions, we have developed a multicenter clinical study protocol and demonstrated its feasibility. To conclude, this thesis work provided a better understanding of the mechanisms of capillary impairments and blunted angiogenesis in COPD patients. While the alteration in the muscle capillary number appeared to be a late process, we showed a novel and early lack of pericyte coverage in these patients. In addition, we were able to identify some actors potentially at the origin of this impairment: the deleterious circulating factors of the disease and some abnormalities of the skeletal muscle cell. The perspective of this thesis will be to better understand the causes and consequences of the pericyte coverage defect during the skeletal muscle angiogenesis in COPD patients.