Introduction: Senescent endothelial cells (ECs) represent 30 to 50% of senescent lung cells during aging and/or development of several lung diseases, including pulmonary hypertension (PH) and emphysema. One potential mechanism is impaired angiogenic vascular endothelial growth factor (VEGF) signalling due to over production of the soluble form of VEGF receptor 1 (sVEGFR1) that trap VEGF.

Objectives: to evaluate the role of impaired VEGF signalling in pulmonary EC senescence during aging, PH and emphysema.

Results: Aged mice compared to young have lower capillary lung density (ICAM+ cells). IP VEGF receptor inhibitor Sugen amplifies these effects and increases the p16+ senescent ECs, decrease ICAM+ cells, impairing pulmonary hemodynamics, and emphysema. Lung sVEGFR1 in mice developing hypoxic PH is increased and worsened by Sugen. In vitro sVEGFR1 leads to patients ECs senescence, while VEGF reduces senescence and improves proliferation. Senescent ECs produce less sVEGFR1 in controls and emphysema patients. Emphysema show higher EC senescence (p16 RNA and B-gal+ cells) and lower cumulative PDL than controls. Furthermore, in all patients, there is a decreased VEGFR1/2 and sVEGFR1 RNA expression in senescent ECs. We generated a mouse model overexpressing VEGF via a constitutive or tissue-specific inducible system (VEGF-TG). Old VEGF-TG mice preserve pulmonary microvascular density, show suppression of p16+ cells and protection against emphysema. Mice overexpressing sVEGFR1 will be studied. 

Conclusion: Enhanced VEGF signalling protects against pulmonary EC senescence and emphysema during aging, with expected protective effects on the development of PH.