Cell senescence in pulmonary hypertension

Pulmonary hypertension (PH) occurring as a primary disease or associated with an underlying lung disease is due to the proliferation of vascular smooth muscle and endothelial cells, which increases pulmonary vascular resistance and ultimately leads to right ventricular failure. Senescent cells exhibiting DNA damage are found at sites of vascular hypertrophy. In mouse models, the induction of cell senescence via nutlin treatment or telomerase deficiency protects against PH. Reciprocally, transgenic mice depleted in p53, p21, or p16 develop more severe PH than their nonmutant counterparts. Eliminating senescent cells by means of genetic or senolytic strategies may aggravate experimental PH, possibly via inhibition of lung angiogenic processes. In some animal models, however, pharmacological senolysis reversed PH as a result of inhibition of the growth-promoting effects of senescence-associated secretory phenotype components. These findings illustrate the complex interplay between senescent and proliferating cells during PH progression and invite consideration of the potential impact of senolytic strategies on pulmonary vessels in various contexts.