Pulmonary arterial hypertension is characterized by vascular remodeling associated with obliteration of pulmonary arterioles and formation of plexiform lesions comprised of hyperproliferative endothelial and vascular smooth muscle cells. Here, we describe a novel, microRNA-dependent association between APLN and FGF2 pathways in the pulmonary artery endothelial cells (PAECs), where disruption of APLN signaling results in a robust increase in FGF2 expression. We show that this link is mediated by two microRNAs, miR-424 and miR-503, that are regulated by APLN and significantly downregulated in PAH. MiR-424 and miR-503 exert anti-proliferative effects by targeting FGF2 and FGFR1. Overexpression of miR-424 and miR-503 in PAECs promoted cellular quiescence and inhibited the capacity of PAEC conditioned media to induce proliferation of pulmonary artery smooth muscle cells. We show that reconstitution of miR-424 and miR-503 can ameliorate pulmonary hypertension in experimental models. These studies demonstrate the importance of APLN-miR-424/503-FGF axis in maintaining pulmonary vascular homeostasis.

BackgroundVarious cancer cells, including those of colorectal cancer (CRC), release microvesicles (exosomes) into surrounding tissues and peripheral circulation. These microvesicles can mediate communication between cells and affect various tumor-related processes in their target cells.ResultsWe present potential roles of CRC cell-derived microvesicles in tumor progression via a global comparative microvesicular and cellular transcriptomic analysis of human SW480 CRC cells. We first identified 11,327 microvesicular mRNAs involved in tumorigenesis-related processes that reflect the physiology of donor CRC cells. We then found 241 mRNAs enriched in the microvesicles above donor cell levels, of which 27 were involved in cell cycle-related processes. Network analysis revealed that most of the cell cycle-related microvesicle-enriched mRNAs were associated with M-phase activities. The integration of two mRNA datasets showed that these M-phase-related mRNAs were differentially regulated across CRC patients, suggesting their potential roles in tumor progression. Finally, we experimentally verified the network-driven hypothesis by showing a significant increase in proliferation of endothelial cells treated with the microvesicles.ConclusionOur study demonstrates that CRC cell-derived microvesicles are enriched in cell cycle-related mRNAs that promote proliferation of endothelial cells, suggesting that microvesicles of cancer cells can be involved in tumor growth and metastasis by facilitating angiogenesis-related processes. This information will help elucidate the pathophysiological functions of tumor-derived microvesicles, and aid in the development of cancer diagnostics, including colorectal cancer.

In this paper, we propose a novel edge-labeling graph neural network (EGNN), which adapts a deep neural network on the edge-labeling graph, for few-shot learning. The previous graph neural network (GNN) approaches in few-shot learning have been based on the node-labeling framework, which implicitly models the intra-cluster similarity and the inter-cluster dissimilarity. In contrast, the proposed EGNN learns to predict the edge-labels rather than the node-labels on the graph that enables the evolution of an explicit clustering by iteratively updating the edgelabels with direct exploitation of both intra-cluster similarity and the inter-cluster dissimilarity. It is also well suited for performing on various numbers of classes without retraining, and can be easily extended to perform a transductive inference. The parameters of the EGNN are learned by episodic training with an edge-labeling loss to obtain a well-generalizable model for unseen low-data problem. On both of the supervised and semi-supervised few-shot image classification tasks with two benchmark datasets, the proposed EGNN significantly improves the performances over the existing GNNs.

Endothelial cells that line the inner walls of blood vessels are in direct contact with blood and display remarkable heterogeneity in their response to exogenous stimuli. These ECs have unique location-dependent properties determined by the corresponding vascular beds and play an important role in regulating the homeostasis of the vascular system. Evidence suggests that vascular endothelial cells exposed to various environments undergo dynamic phenotypic switching, a key biological program in the context of endothelial heterogeneity, but that might result in EC dysfunction and, in turn, cause a variety of human diseases. Emerging studies show the importance of endothelial to mesenchymal transition (EndMT) in endothelial dysfunction during inflammation. EndMT is a complex biological process in which ECs lose their endothelial characteristics, acquire mesenchymal phenotypes, and express mesenchymal cell markers, such as alpha smooth muscle actin and fibroblast-specific protein 1. EndMT is induced by inflammatory responses, leading to pathological states, including tissue fibrosis, pulmonary arterial hypertension, and atherosclerosis, via dysfunction of the vascular system. Although the mechanisms associated with inflammation-induced EndMT have been identified, unraveling the specific role of this phenotypic switching in vascular dysfunction remains a challenge. Here, we review the current understanding on the interactions between inflammatory processes, EndMT, and endothelial dysfunction, with a focus on the mechanisms that regulate essential signaling pathways. Identification of such mechanisms will guide future research and could provide novel therapeutic targets for the treatment of vascular diseases.

Objective The G-protein–coupled receptor APJ and its ligand apelin are highly expressed in the pulmonary vasculature, but their function in this vascular bed is unclear. We hypothesized that disruption of apelin signaling would lead to worsening of the vascular remodeling associated with pulmonary hypertension (PH). Methods and Results We found that apelin-null mice developed more severe PH compared with wild-type mice when exposed to chronic hypoxia. Microcomputed tomography of the pulmonary arteries demonstrated significant pruning of the microvasculature in the apelin-null mice. Apelin-null mice had a significant reduction of serum nitrate levels. This was secondary to downregulation of endothelial nitric oxide synthase (eNOS), which was associated with reduced expression of Kruppel-like factor 2, a known regulator of eNOS expression. In vitro knockdown studies targeting apelin in human pulmonary artery endothelial cells demonstrated decreased eNOS and Kruppel-like factor 2 expression, as well as impaired phosphorylation of AMP-activated kinase and eNOS. Moreover, serum apelin levels of patients with PH were significantly lower than those of controls. Conclusion These data demonstrate that disruption of apelin signaling can exacerbate PH mediated by decreased activation of AMP-activated kinase and eNOS, and they identify this pathway as a potentially important therapeutic target for treatment of this refractory human disease.