Rationale: Pulmonary arterial hypertension is characterized by endothelial dysregulation, but global changes in gene expression have not been related to perturbations in function.Objectives: RNA sequencing was used to discriminate changes in transcriptomes of endothelial cells cultured from lungs of patients with idiopathic pulmonary arterial hypertension versus control subjects and to assess the functional significance of major differentially expressed transcripts.Methods: The endothelial transcriptomes from the lungs of seven control subjects and six patients with idiopathic pulmonary arterial hypertension were analyzed. Differentially expressed genes were related to bone morphogenetic protein type 2 receptor (BMPR2) signaling. Those down-regulated were assessed for function in cultured cells and in a transgenic mouse.Measurements and Main Results: Fold differences in 10 genes were significant (P , 0.05), four increased and six decreased in patients versus control subjects. No patient was mutant for BMPR2. However, knockdown of BMPR2 by siRNA in control pulmonary arterial endothelial cells recapitulated 6 of 10 patient-related gene changes, including decreased collagen IV (COL4A1, COL4A2) and ephrinA1 (EFNA1). Reduction of BMPR2-regulated transcripts was related to decreased b-catenin. Reducing COL4A1, COL4A2, and EFNA1 by siRNA inhibited pulmonary endothelial adhesion, migration, and tube formation. In mice null for the EFNA1 receptor, EphA2, versus control animals, vascular endothelial growth factor receptor blockade and hypoxia caused more severe pulmonary hypertension, judged by elevated right ventricular systolic pressure, right ventricular hypertrophy, and loss of small arteries. Conclusions:The novel relationship between BMPR2 dysfunction and reduced expression of endothelial COL4 and EFNA1 may underlie vulnerability to injury in pulmonary arterial hypertension.

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Background: There is minimal information regarding the prevalence of intratumoral adipose in renal cell carcinoma (RCC), and no study has assessed the impact of intratumoral adipose on the preoperative imaging diagnosis. The aim of this study was to investigate the prevalence and histopathologic characteristics of entrapped adipose with or without osseous metaplasia in RCC nephrectomy specimens and to determine if this finding impacted the preoperative imaging interpretation. Methods: 704 RCC specimens were prospectively evaluated for entrapped adipose and osseous metaplasia (423 partial nephrectomies, 281 total nephrectomies; 327 pT1a, 377 ≥ pT1b; 510 clear cell, 119 papillary, 30 chromophobe, 22 clear cell papillary, 23 other). Imaging reports were obtained, and the presence of intratumoral fat or calcification and the radiologic diagnostic impression were recorded. Results: 3% (n = 21) contained microscopically identified intratumoral adipose, with a similar frequency in the main histologic subtypes (p = 0.76). Mean metaplastic deposit size was 0.4 cm, mean deposit to capsule distance 0.2 cm, and 29% involved the tumor capsule. Histologically identified adipose was infrequently noted via imaging (13%), and only 1 case with histologically identified metaplasia had a radiologic diagnostic differential of angiomyolipoma (1/704, 0.1%). Conclusion: While intratumoral adipose and/or osseous metaplasia can be observed within RCC, it is extremely rare for the radiologic diagnostic impression to have been confounded by histologically identified entrapped adipose. Awareness that metaplastic deposits are usually near the tumor capsule and may be minute could help prevent errors in diagnosis or staging.