Dysregulation of vascular stiffness and cellular metabolism occurs early in pulmonary hypertension (PH). However, the mechanisms by which biophysical properties of the vascular extracellular matrix (ECM) relate to metabolic processes important in PH remain undefined. In this work, we examined cultured pulmonary vascular cells and various types of PH-diseased lung tissue and determined that ECM stiffening resulted in mechanoactivation of the transcriptional coactivators YAP and TAZ (WWTR1). YAP/TAZ activation modulated metabolic enzymes, including glutaminase (GLS1), to coordinate glutaminolysis and glycolysis. Glutaminolysis, an anaplerotic pathway, replenished aspartate for anabolic biosynthesis, which was critical for sustaining proliferation and migration within stiff ECM. In vitro, GLS1 inhibition blocked aspartate production and reprogrammed cellular proliferation pathways, while application of aspartate restored proliferation. In the monocrotaline rat model of PH, pharmacologic modulation of pulmonary vascular stiffness and YAP-dependent mechanotransduction altered glutaminolysis, pulmonary vascular proliferation, and manifestations of PH. Additionally, pharmacologic targeting of GLS1 in this model ameliorated disease progression. Notably, evaluation of simian immunodeficiency virus–infected nonhuman primates and HIV-infected subjects revealed a correlation between YAP/TAZ–GLS activation and PH. These results indicate that ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis and anaplerosis, and thereby link mechanical stimuli to dysregulated vascular metabolism. Furthermore, this study identifies potential metabolic drug targets for therapeutic development in PH.

Human metapneumovirus (hMPV) is a recently discovered human virus that causes significant respiratory infections. Pathologic features of hMPV infection have not been described. A total of 1257 pediatric respiratory samples submitted for routine clinical virologic testing were additionally tested for hMPV by reverse transcriptase polymerase chain reaction (PCR). Pathology specimens, available in 6 of 53 hMPV-positive patients, were examined by light and electron microscopy and included 6 bronchoalveolar lavage (BAL) and 3 lung biopsy specimens from 6 patients (3 girls and 3 boys) ranging in age from 1 to 16 years. BAL from three patients performed within 4 days of the positive hMPV assay showed epithelial degenerative changes and eosinophilic cytoplasmic inclusions within epithelial cells, multinucleate giant cells, and histiocytes. Inclusions were not seen in three patients with BAL performed ≥ 1 month from the time of their positive assay. Lung biopsy, performed in three patients, all ≥ 1 month from the time of their positive assay, showed chronic airway inflammation and intraalveolar foamy and hemosiderin-laden macrophages; all three patients had an underlying pulmonary/systemic disorder. Our findings delineate the clinico-pathologic features in hMPV-infected patients undergoing anatomic sampling, which may provide diagnostic guidance to a practicing pathologist. Further, they contribute toward understanding the pathogenesis of hMPV infection.

Only two karyotypes of perineurioma have previously been reported, 46XX,del(10)(q22q24),der(10),del(22)(q11-12q?)/47, idem,+der(10) (in a sclerosing perineurioma of the finger) and 45,XX,add(14)(p13),-22,add(22)(q11.2) (in an intraneural perineurioma). We investigated the clinicopathologic and cytogenetic findings in four consecutive perineuriomas in children, including two small (≤1 cm) digital sclerosing perineuriomas, a 2-cm intraneural perineurioma, and a 16-cm abdominal soft tissue perineurioma. All lesions showed plump perineurial cells in a complex whorled configuration. Immunohistochemical (strong EMA immunostaining in all cases) and ultrastructural (in three of three lesions examined) evidence of perineurial differentiation was present. The sclerosing perineuriomas showed 46,XY,t(2;10)(p23;q24) and 47,XX,add(3)(q23),add(6)(q21),-5,-9,-10,-22,+mar1,+mar2,+mars; the intraneural tumor showed 46,XX,add(2)(q11.2),add(3)(q12); and the abdominal soft tissue perineurioma showed 46,XX,t(8;9)(q13;q22). Metaphase FISH analysis for an ALK gene rearrangement in the sclerosing perineurioma with t(2;10) was negative; the ALK signal remained on the der(2). We conclude that perineuriomas display mostly simple karyotypes, characterized by one or few chromosomal rearrangements or numerical changes. In conjunction with the previously published sclerosing perineurioma karyotypes, the findings of chromosome 10 aberrations, t(2;10)(p23;q24) and monosomy 10 in two sclerosing perineuriomas, indicate that rearrangements and/or deletions of 10q are a consistent finding in this variant of perineurioma. The findings also expand previous assertions that chromosome 22 abnormalities are pathogenetic in perineurioma and suggest that diverse genetic tumorigenic mechanisms may exist, possibly depending on the subtype.

We report a distinctive lesion of the labium majus resected in 14 girls from 3.9 to 13.2 years of age. All presented with enlargement of 1 or occasionally both labia majora. Radiographic imaging and surgical exploration showed expansion of the labium majus without definable borders. Grossly, specimens consisted of fibro-fatty tissue from 2 to 8 cm in greatest dimension. Microscopic examination revealed the usual constituents of vulvar soft tissue, with expansion of the fibrous component. Sparsely to moderately cellular interconnected bands encircled lobules of fat, blood vessels, and nerves. The bands consisted of plump and occasionally stellate or round fibroblasts immersed in an abundant pale myxoid matrix containing thin collagen fibers. These fibrous bands merged with thinner denser fibrous septa simlar to those seen in the vulva from age-matched controls. Elastic stains showed variably abundant thin parallel elastic fibers. Fibroblasts were immunohistochemically positive for estrogen and progesterone receptors. Electron microscopy showed fibroblasts with dilated rough endoplasmic reticulum cisternae and prominent nuclear fibrous laminae; extracellular matrix contained precollagen, collagen, elastic fibers, and numerous proteoglycan granules. Cytogenetic analysis of 3 lesions revealed a normal karyotype. Recurrence was observed in 7 (50%) patients, and regression was observed in 1 whose recurrence was not reexcised. Over an 11-year period at Children's Hospital (Boston, MA), these lesions represented 22% of all pediatric vulvar soft tissue masses and 3% of all vulvar lesions biopsied. We conclude that “childhood asymmetric labium majus enlargement” is a distinctive clinicopathologic entity of pre- and early puberty. Recognition of this fairly common lesion is important, since it may clinically, radiographically, and histologically mimic an infiltrative neoplasm. Its occurrence at an age roughly coincident with the time of breast budding, capacity for spontaneous regression, histologic architecture and composition of elements native to the vulva, expression of hormone receptors, and normal karyotype suggest that it is an asymmetric physiologic enlargement in response to hormonal surges of pre- and early puberty.

Vascular remodeling is the process of structural alteration and cell rearrangement of blood vessels in response to injury and is the cause of many of the world’s most afflicted cardiovascular conditions, including pulmonary arterial hypertension (PAH). Many studies have focused on the effects of vascular endothelial cells and smooth muscle cells (SMCs) during vascular remodeling, but pericytes, an indispensable cell population residing largely in capillaries, are ignored in this maladaptive process. Here, we report that hypoxia-inducible factor 2α (HIF2α) expression is increased in the lung tissues of PAH patients, and HIF2α overexpressed pericytes result in greater contractility and an impaired endothelial-pericyte interaction. Using single-cell RNAseq and hypoxia-induced pulmonary hypertension (PH) models, we show that HIF2α is a major molecular regulator for the transformation of pericytes into SMC-like cells. Pericyte-selective HIF2α overexpression in mice exacerbates PH and right ventricular hypertrophy. Temporal cellular lineage tracing shows that HIF2α overexpressing reporter NG2+ cells (pericyte-selective) relocate from capillaries to arterioles and co-express SMA. This novel insight into the crucial role of NG2+ pericytes in pulmonary vascular remodeling via HIF2α signaling suggests a potential drug target for PH.