Significance: Caveolin-1 (CAV1) loss-of-function mutations are a hereditary cause of pulmonary arterial hypertension (PAH), but wild-type CAV1 is also decreased in the vascular lesions of idiopathic and disease-associated PAH. Using human pulmonary artery endothelium, lung tissue, and serum from Cav1 ^−/− mice, as well as fibroblasts and serum from patients with CAV1 mutations, CAV1 deficiency produced a dysfunctional, PAH-like endothelial phenotype driven by an interferon-biased inflammatory response with constitutive STAT and AKT activation. Inhibiting JAK/STAT and PI3K/AKT reversed the aberrant endothelial phenotype of CAV1 loss and may similarly ameliorate pathologic vascular remodeling in PAH. Exogenous interferon alone reduced CAV1 expression and activated these same signaling pathways, suggesting that CAV1 insufficiency may contribute to the development of autoimmune and autoinflammatory disease-associated PAH.

Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease characterized by pathologic vascular remodeling of small pulmonary arteries. Endothelial dysfunction in advanced PAH is associated with proliferation, apoptosis resistance, and endothelial to mesenchymal transition (EndoMT) due to aberrant signaling. DLL4, a cell membrane associated NOTCH ligand, plays a pivotal role maintaining vascular integrity. Inhibition of DLL4 has been associated with the development of pulmonary hypertension, but the mechanism is incompletely understood. Here we report that BMPR2 silencing in pulmonary artery endothelial cells (PAECs) activated AKT and suppressed the expression of DLL4. Consistent with these in vitro findings, increased AKT activation and reduced DLL4 expression was found in the small pulmonary arteries of patients with PAH. Increased NOTCH1 activation through exogenous DLL4 blocked AKT activation, decreased proliferation and reversed EndoMT. Exogenous and overexpression of DLL4 induced BMPR2 and PPRE promoter activity, and BMPR2 and PPARG mRNA in idiopathic PAH (IPAH) ECs. PPARγ, a nuclear receptor associated with EC homeostasis, suppressed by BMPR2 loss was induced and activated by DLL4/NOTCH1 signaling in both BMPR2-silenced and IPAH ECs, reversing aberrant phenotypic changes, in part through AKT inhibition. Directly blocking AKT or restoring DLL4/NOTCH1/PPARγ signaling may be beneficial in preventing or reversing the pathologic vascular remodeling of PAH.

Lymphocyte depletion is a distinctive feature of Ebola virus (EBOV) disease. The ectodomain of EBOV glycoprotein (GP) is cleaved off the surface of infected cells into circulation as shed GP. To test the hypothesis that shed GP induces lymphocyte death, we cultured primary human B, NK, or T cells with shed GP in vitro. We found that shed GP dependably decreased B, NK, and T cell viability across donors. B and NK cells exhibited higher susceptibility than T cells. Continuous monitoring revealed shed GP began to kill B and NK cells by 4 h and T cells by 5 h. We also demonstrated that shed GP-induced lymphocyte death can be both caspase dependent and caspase independent. Our data are evidence that the cytotoxic effect of shed GP on lymphocytes may contribute to EBOV disease and highlight the need for further research to clarify mechanisms of shed GP-induced death.

Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease characterized by vascular remodeling of small pulmonary arteries. Endothelial dysfunction in advanced PAH is associated with proliferation, apoptosis resistance, and endothelial to mesenchymal transition (EndoMT) due to aberrant signaling. DLL4, a cell membrane associated NOTCH ligand, activates NOTCH1 signaling and plays a pivotal role maintaining vascular integrity. Inhibition of DLL4 has been associated with the development of pulmonary hypertension, but the mechanism is incompletely understood. Here we report that BMPR2 silencing in PAECs activated AKT and decreased DLL4 expression. DLL4 loss was also seen in lungs of patients with IPAH and HPAH. Over-expression of DLL4 in PAECs induced BMPR2 promoter activity and exogenous DLL4 increased BMPR2 mRNA through NOTCH1 activation. Furthermore, DLL4/NOTCH1 signaling blocked AKT activation, decreased proliferation and reversed EndoMT in BMPR2 – silenced PAECs and ECs from IPAH patients. PPARγ, suppressed by BMPR2 loss, was induced and activated by DLL4/NOTCH1 signaling in both BMPR2 -silenced and IPAH PAECs, reversing aberrant phenotypic changes, in part through AKT inhibition. Finally, leniolisib, a well-tolerated oral PI3K8/AKT inhibitor, decreased cell proliferation, induced apoptosis and reversed markers of EndoMT in BMPR2 -silenced PAECs. Restoring DLL4/NOTCH1/PPARγ signaling and/or suppressing AKT activation may be beneficial in preventing or reversing the pathologic vascular remodeling of PAH.

RNA- and protein-based medicines are expanding cardiovascular therapeutic options, but efficient delivery to cardiomyocytes, fibroblasts, vascular cells, and lesional immune cells remains difficult. Target selection also relies disproportionately on European-ancestry datasets, limiting causal resolution and portability. This narrative review evaluates extracellular vesicles (EVs) as carriers and active biological products for cardiovascular RNA and protein therapeutics. We distinguish EVs carrying a defined active ingredient, intrinsically bioactive EV preparations, and EV-inspired synthetic systems. We link delivery design to human multi-omics by integrating diverse-ancestry genome-wide association studies, fine-mapping, molecular quantitative trait loci, colocalization, Mendelian randomization, and single-cell or spatial transcriptomics. Hepatic targets such as PCSK9, LPA, APOC3, ANGPTL3, AGT, and TTR provide benchmarks against which EV platforms can be assessed. The strongest rationale for EVs lies in extrahepatic programs where tissue access limits otherwise compelling myocardial, fibrotic, vascular, or regenerative targets. We propose a stage-gated roadmap connecting causal evidence and cell-state specificity to modality selection, cargo loading, targeting, endosomal escape, biodistribution, human cardiac models, manufacturing, potency, and safety. We then apply the framework to worked examples (LPA, CAMK2D, COL6A3-derived endotrophin, AGER/RAGE, and VEGFA), in which fine-mapping, colocalization, Mendelian randomization, ancestry-specific evidence, and cell-state localization jointly determine the modality and the carrier, including targets for which an EV is not the appropriate choice. Cited delivery studies are graded on a four-level evidence ladder spanning tissue association, intact-cargo delivery, cytosolic release, and pharmacodynamic activity, because most cardiovascular EV reports establish only the lower levels. The cardiovascular EV studies reviewed do not establish clinical benefit or an advantage over optimized lipid nanoparticles at matched active-cargo dose in a cardiovascular disease model. Clinical translation depends on reproducible functional delivery, a defined mechanism, consistent product quality, and meaningful benefit relative to established treatments.