This review summarizes our current knowledge on lung vasculogenesis and angiogenesis during normal lung development and the regulation of fetal and postnatal pulmonary vascular tone. In comparison to that of the adult, the pulmonary circulation of the fetus and newborn displays many unique characteristics. Moreover, altered development of pulmonary vasculature plays a more prominent role in compromised pulmonary vasoreactivity than in the adult. Clinically, a better understanding of the developmental changes in pulmonary vasculature and vasomotor tone and the mechanisms that are disrupted in disease states can lead to the development of new therapies for lung diseases characterized by impaired alveolar structure and pulmonary hypertension.

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Aim: Experiments were designed to determine the mechanism underlying the endothelium‐dependent, soluble guanylyl cyclase‐dependent augmentation caused by thymoquinone in isolated arteries. Methods: Rings, with or without endothelium, of porcine coronary arteries were suspended in conventional organ chambers for isometric tension recording. Certain rings were incubated with inhibitors of nitric oxide (NO) synthase inhibitor (L‐NG‐nitroarginine methyl ester, L‐NAME) or soluble guanylyl cyclase (1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one, ODQ). They were contracted with phenylephrine (rat arteries) or prostaglandin F2α (porcine coronaries) and exposed to increasing concentrations of thymoquinone. Cyclic nucleotides were measured by HPLC‐MS/MS. Results: Thymoquinone caused a sustained further increase of tension in rings with endothelium. This augmentation was prevented by endothelium‐removal, L‐NAME and ODQ. Incubation with the NO‐donor detaNONOate in L‐NAME‐treated rings restored and even increased the contractile response to thymoquinone. Administration of cIMP restored contractions to thymoquinone in rings without endothelium. By contrast; treatment with pyrophospate did not restore the augmentation by thymoquinone. HPLC‐MS/MS measurements revealed that the latter compound increased the production of cIMP while reducing that of cGMP. Conclusion: The endothelium‐dependent augmentation caused by thymoquinone requires endothelium‐derived NO, activation of soluble guanylyl cyclase and production of cIMP but not the presence of either pyrophosphate or cyclic GMP.