Research progress on autophagy-related regulatory pathways of vascular remodeling in pulmonary hypertension

Pulmonary hypertension (PH) is a cardiopulmonary disease with complex etiology, characterized by progressively increasing pulmonary vascular resistance and pulmonary vascular remodeling. Currently, there is no cure for PH, highlighting an urgent clinical need for novel therapeutic targets to intervene in vascular remodeling. Recent research indicates that dysregulation of cellular autophagy plays a pivotal role in the pathogenesis and progression of PH. Autophagy, a highly conserved cellular self-degradation process, precisely regulates the proliferation, apoptosis, migration, and phenotypic switching of pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs) through multiple signaling pathways, thereby influencing the course of pulmonary vascular remodeling. This review aims to systematically elucidate the autophagy-related signaling pathways involved in pulmonary vascular remodeling. These pathways include, but are not limited to, the FoxO1, AMPK-mTOR-ULK1, NF-κB, PI3K/AKT/mTOR, ROS, LC3/Beclin-1, HIF-1α/BNIP3, BMPR2, and MAPK signaling pathways. These pathways form a complex regulatory network. Among them, the FoxO1 and AMPK-mTOR-ULK1 pathways primarily exert protective effects in pulmonary vascular remodeling. In contrast, the NF-κB, eIF2α, LC3/Beclin-1 pathways, oxidative stress, and BMPR2 mutations predominantly contribute to detrimental effects. The HIF-1α/BNIP3, PI3K/AKT/mTOR, and MAPK pathways can play dual roles, finely tuning abnormal PASMC proliferation, migration, and anti-apoptosis, as well as PAEC dysfunction and apoptosis. This intricate regulation ultimately drives or inhibits remodeling processes such as vascular wall thickening and lumen occlusion. Furthermore, this article reviews therapeutic strategies for PH targeting autophagy. By employing pharmacological interventions to either inhibit or promote cellular autophagy, vascular remodeling can be suppressed, thereby alleviating PH. For example, the mTOR inhibitor rapamycin, chloroquine, and hydroxychloroquine are utilized to inhibit autophagy clinically. In addition to drug-based approaches, gene therapy strategies can also be applied to regulate autophagy. Targeting genes such as miR-210, miR-138-5p, miRNA-205-5p, miR-204, and miR-382-3p can reduce the proliferation, differentiation, and anti-apoptotic activity of PASMCs, decrease medial hypertrophy in the pulmonary vasculature in experimental PH, and consequently attenuate pulmonary vascular remodeling. An in-depth exploration of the regulatory role of autophagy in pulmonary vascular remodeling will contribute to advancing research on the molecular mechanisms of PH and facilitate the development of autophagy-related therapeutics. It is believed that with further investigation into the molecular mechanisms of autophagy in PH, autophagy is likely to become a breakthrough point and a crucial target for the prevention and treatment of PH.