Endothelial injury and vascular reactivity in monocrotaline pulmonary hypertension

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Abstract
We used awake, unsedated rats with indwelling cardiovascular catheters to study the role of endothelial injury and increased pulmonary vascular reactivity in the pathogenesis of monocrotaline (MC)-induced pulmonary hypertension. Hemodynamic findings were correlated with morphometric analyses of alterations in the vascular endothellium assessed by electron microscopy and of muscularization of pulmonary arteries assessed by light microscopy. Male Sprague-Dawley rats (200-250 g) were injected with MC (60 mg/kg) or with saline vehicle. The hemodynamic response to acute hypoxia (10% O2 for 10 min) was studied at 4, 8, and 12 days postinjection. Pulmonary artery pressures and resistances (Ppa, Rp) were similar in saline- and MC-injected rats at 4 and 8 days postinjection. In response to acute hypoxia, the rise in Ppa was also similar, but there was a slight but significant rise in R1p, (P < 0.05) in the 8-day group, due largely to a decrease in cardiac output. At 12 days after injection, base-line Ppa wa increased in MC-injected rats (P < 0.01) and there was a heightened response to hypoxia assessed both as a significant increase in Ppa and Rp (P < 0.05 each). Endothelial injurywas observed as early as 4 days postinjection with pallor and swelling evident qualitatively and by a decreased proportion of microfilaments (P < 0.05) assessed quantitatively. By light microscopy, extension of smooth muscle into normally nonmuscularized pulmonary arteries was evident by 8 days postinjection. By 12 days postinjection there was marked extension of smooth muscle present (P < 0.01) with medial hypertrophy of muscular arteries. Thus increased vascular reactivity does not account for the structural changes and severe pulmonary hypertension in this model.