Plexiform Lesion in Severe Pulmonary Hypertension: Association with Glomeruloid Lesion

To the Editor-in-Chief:

Sundberg et al 1 have recently described the formation of glomeruloid bodies in ears of athymic mice injected with a nonreplicating adenovirus engineered to express the 164-amino-acid form of the vascular permeability factor/vascular endothelial growth factor (VPF/VEGF).This important work contributes significantly to our current understanding of the vascular proliferation associated with malignancies such as glioblastoma multiforme, in that it demonstrates that VPF/VEGF expression suffices to induce these lesions.

To the list of pathological processes associated with the glomeruloid lesion, we wish to add the plexiform lesion present in severe pulmonary hypertension. Severe pulmonary hypertension, a condition associated with marked elevation of pulmonary artery pressures, heart failure, and high mortality, may present with the formation of plexiform lesions in medium sized pulmonary arteries. We had previously demonstrated that plexiform lesions are composed of proliferated endothelial cells. 2,3 We have proposed that the endothelial cell proliferation in plexiform lesions occurs via a process of disordered angiogenesis since the endothelial cells express VPF/VEGF, VEGF receptor II or KDF, HIF-α and HIF1-β (aryl receptor hydrocarbon translocator (ARNT)). 4 The partnership of HIF1-α and HIF1-β, leading to the formation of the hypoxia inducible factor (HIF) transcription factor may activate the expression of VEGF, among numerous genes that are induced by hypoxia.

Plexiform lesions form ubiquitously as a growth of endothelial cells within the lumen of small precapillary pulmonary arteries, and early clusters of endothelial cells in these lesions strikingly resemble the early stages of formation of the glomeruloid lesion as shown in Figure 1B by Sundberg et al. However, in contrast to the fact that the expression of VPF/VEGF is in cells outside the glomeruloid lesions described by Sundberg et al and in malignant glioblastoma cells surrounding the glomeruloid endothelial cell hyperplasia, 5 the endothelial plexiform lesions appear to express both VPF/VEGF and its receptor II. Such a pattern of gene expression, suggestive of an autocrine action of VEGF on its receptor II, has been characteristically described in neoplastic endothelial cell processes.

The resemblance of the endothelial cell proliferation in plexiform lesion to neoplasia is further supported by the fact that endothelial cells in idiopathic forms of severe pulmonary hypertension, also called primary or idiopathic pulmonary hypertension, are monoclonal whereas the morphologically identical plexiform lesions in severe pulmonary hypertension associated with congenital heart malformations are polyclonal. 6 In line with the finding that the endothelial cells in primary pulmonary hypertension are monoclonal, we have recently reported microsatellite instability and mutations in microsatellite sites of the endothelial cell growth regulatory genes transforming growth factor-β receptor II and Bax. 7 Impaired transforming growth factor-β signaling likely impairs apoptosis in the plexiform lesions’ endothelial cells and could permit increased VEGF gene expression. An animal model of the glomeruloid lesions such as the one described by Sundberg et al 1 may aid in the elucidation not only of similar lesions in cancer but also in the pathogenesis of plexiform lesions in severe pulmonary hypertension.