Abstract: AIM To investigate the possible mechanism of the effect of chronic neuropathic pain on the development of hypoxic pulmonary hypertension. METHODS Thirty male Sprague Dawley (SD) rats were randomized into 5 groups: normoxia, chronic pain+normoxia, hypoxia, chronic pain+hypoxia, and chronic pain+hypoxia+Alda1, with 6 rats in each group. The classical chronic compression of dorsal root ganglia (CCD) model was utilized to replicate chronic neuropathic pain in the rats. After establishment of chronic neuropathic pain in all of the rats, they were exposed to a hypobaric hypoxia environment for 4 weeks to establish a hypoxic pulmonary hypertensive state. Endothelium-intact pulmonary artery rings (PAs) from all groups of rats were isolated to detect changes of relaxation and contraction. Then, circulating 4-HNE levels were recorded and expression of ALDH2 on pulmonary arteries was measured. RESULTS Hypoxia decreased diastolic function of PAs (P<0.05) and enhanced systolic function of PAs (P<0.05). Worse dysfunction of diastolic and systolic functions was seen in PAs from chronic pain+hypoxia group rats (P<0.01, respectively). Hypoxia promoted circulating 4-HNE levels (P<0.01), and circulating 4-HNE levels increased more significantly in chronic pain+hypoxia group rats (P<0.01), suggesting a large amount of 4-HNE induced by long-term chronic neuropathic pain may cause worse dysfunction of diastolic and systolic function of PAs. Use of the aldehyde dehydrogenase (Aldehyde dehydrogenase, ALDH)2 agonist Alda1 significantly improved the worse dysfunctions of diastolic and systolic function of PAs induced by chronic pain and hypoxia (P<0.01, respectively), up-regulated expression of ALDH2 (P<0.01) and decreased circulating 4-HNE levels (P<0.01). CONCLUSION Chronic neuropathic pain increased circulating 4-HNE level, decreased the expression of ALDH2 on pulmonary arteries, promoted and aggravated the dysfunctions of relaxation and contraction of PAs and therefore, accelerated development of HPH.