The Geometry of the Progression of Occlusive Lesions in Severe Pulmonary Arterial Hypertension

The vasculopathy of pulmonary arterial hypertension (PAH) includes the hallmark of occlusive, plexogenic lesions in pulmonary microvessels. Traditional studies of vascular lesions in PAH have relied on two‐dimensional histological preparations to grade and characterize lesion incidence and severity. However, this approach fails to acknowledge the physiological structure of vascular lesions in situ , and may systematically misidentify key anatomical features of the lung vasculature such as supernumerary arteries and vessel branching patterns. Therefore, we employed a three‐dimensional approach to composite serial histological lung sections to examine the geometry of vascular lesions in PAH. In light of recent three‐dimensional studies of vascular morphology in PAH which demonstrate that the progression of occlusive lesions has both temporal and spatial components, we tested the hypothesis that occlusive lesions within pulmonary microvessels in PAH exhibit patterns of severity along the length of vessel segments. Using Sugen/hypoxia treated hypertensive rats, we found that the incidence of occlusive lesions was undercounted with a conventional histological approach, due to the inability of cross‐sectional analysis to identify vascular trees linked in three‐dimensional space. Furthermore, we found that lesion severity was a complex function of vessel diameter, where disorganized lesions increased with decreased vessel diameter but were surrounded by a continuum of lesion grades. These results suggest that the contribution of occlusive lesions to the pathophysiology of PAH may be under represented, and underscore the necessity of three‐dimensional anatomical characterization of PAH vasculopathy. Support or Funding Information This work was funded by NIH grants HL60024 and HL66299