Flow-activated transcription factor Krüppel-like factor 2 (KLF2) signaling is compromised in pulmonary arterial hypertension (PAH). We aimed to identify KLF2-induced endotheliumprotective exosomal microRNAs of potential therapeutic significance. Eight exosomal microRNAs elevated by KLF2 but reduced in PAH were transfected into human pulmonary artery endothelial cells. Of these, only miR-181a-5p and miR-324-5p had anti-apoptotic, anti-inflammatory and anti-proliferative effect on endothelial cells and reduced proliferation of vascular smooth muscle cells in vitro. RNA sequencing of miRNAtransfected HPAECs revealed reduced expression of multiple genes implicated in vascular remodelling, including ETS-1, NOTCH4, ACTA2, TNF-α, IL-1, MMP10, MAPK and NFATC2. KLF2, miR-181a-5p and miR-324-5p were reduced, while their target genes were elevated in blood-derived endothelial colony forming cells and lung tissues from idiopathic and heritable PAH patients with disabling KLF2 mutation and Sugen/hypoxia mice. Supplementation of miR-181a-5p and miR-324-5p or silencing of their target genes attenuated proliferative and angiogenic responses in endothelial cells from idiopathic PAH and prevented development of pulmonary hypertension in Sugen/hypoxia mice.This study highlights potential therapeutic role of KLF2-induced exosomal microRNAs in PAH.