Novel Insights Into Receptor Tyrosine Kinases in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease with high morbidity, significant mortality, and poor prognosis. To date, the pathogenesis of PAH is still not clarified, and the effectiveness of current treatment strategies is limited. Therefore, it is essential to understand the pathophysiology of PAH and to explore optimal treatment approaches. RTKs (receptor tyrosine kinases) are a family of enzyme-linked receptors that can be bound with specific ligands and then phosphorylate tyrosine residues of substrate targets, playing a crucial role in various biological processes. Accumulating evidence indicates that RTKs are strongly associated with the pathogenesis of PAH. Interestingly, even the same RTK may exhibit opposite effects in PAH under different circumstances. We hypothesize that this may stem from factors such as genetic background, cell line specificity, hypoxia gradient variations, and other underlying mechanisms. Although several RTK-targeting small molecule drugs have entered clinical trials, concerns regarding their toxicity and limited efficacy have been reported. To facilitate the clinical translation of these therapeutic agents, we highlight the pressing need for developing highly selective drugs (eg, monoclonal antibodies) and more sophisticated drug delivery systems. In this review, we therefore summarized and constructed a multilevel regulatory framework of RTKs with PAH pathogenesis, aiming to guide future clinical practice.