Abstract Rationale Endostatin (ES), a C-terminal fragment of collagen XVIII (COL18A1), is an endogenous angiostatic peptide elevated in pulmonary arterial hypertension (PAH) and linked to capillary rarefaction, maladaptive right ventricular remodeling, and increased mortality. Genetic variation in COL18A1 influences ES levels and PAH outcomes, implicating this axis as a causal mediator of vascular maladaptation. We hypothesized that transcriptomic profiling of human lung microvascular endothelial cells (HMVEC-L) exposed to recombinant ES (rES) would define the molecular programs through which ES disrupts endothelial homeostasis and identify potential targets to reverse these effects. Methods HMVEC-Ls were challenged with rES, for 6 hours and analyzed by bulk RNA-sequencing. Differential gene expression (DGE) was performed on the filtered and normalized counts using edgeR. Genes were considered differentially expressed if the FDR was 0.05. Pathway enrichment was evaluated using decoupleR and GSEA with the MSigDB Hallmark and DisGeNET database. To identify compounds predicted to reverse the rES-induced transcriptomic signature, the top 150 up- and downregulated DEGs were queried in the CLUE Connectivity Map platform. Results rES induced a substantial transcriptomic shift, with 3,252 genes upregulated and 3,429 downregulated. Pathway analysis revealed suppression of hypoxia and TGF-β signaling and activation of PI3K-AKT and MAPK pathways. Disease enrichment analysis demonstrated significant overlap with idiopathic PAH gene signatures, in which disease-associated genes were predominantly repressed. CLUE analysis identified PI3K, SRC, and mTOR inhibitors as drug classes predicted to reverse the rES-induced PAH-like signature. Conclusions These findings integrate with prior evidence implicating the COL18A1/ES axis in EC dysfunction and RV maladaptation. The rES signature reflects a maladaptive angiostatic endothelial state, and predicted reversibility by PI3K-mTOR-SRC inhibitors highlights druggable signaling nodes. Selective kinase pathway modulation may counteract ES-driven angiostasis, restore endothelial homeostasis, and improve RV adaptation in PAH This abstract is funded by: NIH HL132153/R01(RLD/PMH)
Berger et al. (Fri,) studied this question.