Lung vascular lesions in pulmonary arterial hypertension (PAH) are characterized by enlarged, vacuolated (megalocytotic) pulmonary arterial endothelial (PAEC) and smooth muscle cells (PASMC). We have recently proposed that dysfunction of vesicle tethers, SNAREs and SNAPs leading to disruptions of intracellular trafficking in the Golgi to plasma membrane (centrifugal) and the plasma membrane to cell interior (centripetal) directions is a key causal mechanism in this disease. In PAH, there was a reciprocal relationship between loss of caveolin-1 (cav-1) in PAECs and increase in "activated" PY-STAT3 together with a block in centrifugal trafficking to/through the Golgi organelle. In the present study we investigated whether (a) centripetal trafficking of STAT3 and PY-STAT3 in PAECs and PASMCs was membrane-associated, and (b) whether this might be affected in PAH. Immunofluorescence and live-cell imaging studies showed that in both PAEC and PASMC, STAT3 was associated with cytoplasmic vesicles partially colocalizing with markers of the endolysosomal compartments (clathrin, EEA1, Rab5, Rab11 and LAMP1). Overexpression of cav-1 increased the targeting of STAT3 to lysosomes and inhibited STAT3 transcriptional activity. Exposure of PAECs to monocrotaline pyrrole (MCTP), which causes PAH in the rat, led to a loss of caveolar STAT3 with increased sequestration of STAT3 and PY-STAT3 in endosomes. In vivo, marked cytoplasmic sequestration of activated PY-STAT3 was a common feature in PAEC in the rat/MCT model and in cells in the proliferative arterial and plexiform lesions in PAH in man. These data highlight the epigenetic regulation of centripetal cytokine and growth-factor signaling pathways and its modulation in PAH.