Volume 2 Issue 6, June 2023

Vascular patterning is dictated by transcription factors, such as the Notch pathway. Molecular profiling has uncovered snapshots of the transcriptional specification of endothelial cell tubulogenesis. Here, the authors leverage the output of Notch signaling, demonstrating that vascular remodeling is poorly predicted by transcriptional profiling.

Ranolazine is an anti-arrhythmic drug that targets voltage-gated sodium channels. Lenaeus et al. present a cryo-EM structure of the cardiac sodium channel bound to ranolazine to demonstrate that this compound acts as a structural clamp that inhibits the channels.

The plasma of individuals with atherosclerosis contains cytokines that induce a pathogenic signaling cascade in immune cells. Saracatinib, a dual kinase inhibitor that targets the tyrosine kinases SRC and BCR-ABL, can prevent activation of this phospho-signaling pathway implicated in the pathogenesis of cardiovascular disease.

Targeting the Notch ligand DLL4 in adult liver vessels induced transcriptional states associated with endothelial cell (EC) proliferation and sprouting. However, genetic and pharmacological inhibition of these angiogenic cell states did not prevent an abnormal vasculature and pathology in the liver, suggesting that transcriptional states do not always inform on the vascular phenotype and related pathophysiology.

Modeling complex immune responses to decipher and target the underlying inflammatory mechanisms of atherosclerotic cardiovascular disease (ASCVD) in humans has been challenging. By combining systems immunology-driven drug repurposing with drug functional screens directly in human samples, we identified a new anti-atherosclerotic use for the dual kinase inhibitor saracatinib.

Our study demonstrates that statins improve endothelial function and vascular health by inhibiting the epigenetic activation of the YAP–SOX9 signaling axis and subsequently preventing endothelial-to-mesenchymal transition in conditions associated with an increased risk of cardiovascular disease, such as type 2 diabetes.

Flam and Arany review the current knowledge of how the signaling intermediate metabolites affect the heart in health and disease.

Aitken and colleagues discuss the current understanding of how endothelial cells sense blood flow, focusing on the mechanosensing and mechanotransduction molecules and mechanisms, and highlighting challenges and outstanding questions that should lead future research efforts.

Fernández-Chacón et al. use imaging and scRNA-seq after targeting multiple Notch genes and angiogenic signaling pathways to find that the function of these pathways in vascular pathophysiology cannot be predicted by assessing transcriptional states.

Amadori et al. show that plasma from patients with atherosclerosis triggers unique inflammatory transcriptomic and signaling signatures in peripheral blood mononuclear cells, which were used for selecting drugs that may be repurposed for the treatment of atherosclerosis.

Liu et al. report that the IL-6R antibody reduces the atherosclerosis promoted by Tet2 clonal hematopoiesis (CH) via reversal of increased macrophage colony-stimulating factor 1 receptor expression and suggests blocking IL-6 signaling as a potential therapy for CH-driven cardiovascular disease.

Lenaeus et al. use a combination of mutagenesis, electrophysiology and cryogenic electron microscopy to define the interaction of the antianginal and antiarrhythmic ranolazine, with the sodium channel Na_V1.5 at high resolution, thus revealing the binding pose and distinct molecular interactions underlying the favorable pharmacological characteristics of this drug, which present fewer proarrhythmic effects than class I antiarrhythmic drugs.

Seront et al. report a case of successful management of high-risk cervicofacial fetal lymphatic malformations in utero via sirolimus taken orally by the mother from the 22nd week of pregnancy until 2 weeks before planned delivery.