Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease caused by a mutation in LMNA, leading to the expression of a prelamin A variant called progerin. HGPS hallmarks include accelerated cardiovascular disease and atherosclerosis, caused in part by ER stress-induced apoptosis of vascular smooth muscle cells. As a dysregulated unfolded protein response (UPR) can induce endothelial cell (EC) pathology during aging, we investigated whether loss of proteostasis contributes to EC dysfunction in HGPS, using an endothelium-specific HGPS mouse model. Contrary to previous reports in vascular smooth muscle cells and fibroblasts, we found no robust activation of UPR in ECs constitutively expressing progerin, and cells retained the ability to elicit potent UPR when exposed to external ER stress. Unlike aortic tissue derived from mice with endothelium-specific progerin expression, aorta from Lmna G609G/+ mice with ubiquitous progerin expression showed up-regulation of the UPR, suggesting that the UPR in HGPS aorta is primarily rooted in non-ECs. Analysis of scRNA-Seq datasets from aorta in Lmna G609G/G609G mice confirmed this hypothesis. Our data indicate that UPR activation is a cell-type-specific phenomenon in progerin-expressing arteries.
© 2025 Silva et al.

ATP-binding cassette B8 (ABCB8) is a mitochondrial iron exporter known to prevent iron-dependent oxidative stress in cardiomyocytes and endothelial cells. However, the role of ABCB8 in endothelial and vascular function remains unclear. Here, we identified ABCB8 as a key regulator of vascular homeostasis. We found that loss of ABCB8 in endothelial cells triggers a pro-inflammatory transcriptional program, marked by upregulation of TGF-β isoforms and activation of TGF-β signalling. We show that TGF-β functions as an iron effector that drives mitochondrial reactive oxygen species (ROS) and mitochondrial damage, revealing a new ABCB8-iron-TGF-β axis in endothelial cells. In endothelial-specific inducible Abcb8 knockout mice (Abcb8ECKO), ABCB8 deficiency leads to endothelial activation, pro-inflammatory transcriptional reprogramming of smooth muscle cells (SMCs), fibroblasts and immune cells. Combination of intravital imaging experiments with ex vivo treatment of aortae from Abcb8ECKO with the iron chelator deferoxamine or TGF-β receptor I inhibitor SB431542 suggests that ABCB8 suppresses iron-dependent TGF-β-mediated vascular inflammation in the aorta. In agreement, endothelial ABCB8 deficiency exacerbates atherosclerosis and hypertension in Apoe-/- knockout mice, uncovering a critical atheroprotective role for ABCB8 and supporting its therapeutic potential in vascular disease.
Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.

Angiotensin-II (Ang-II) drives pathological vascular wall remodeling in hypertension and abdominal aortic aneurysm (AAA) through mechanisms that are not completely understood. Previous studies showed that the phosphatase activity of calcineurin (Cn) mediates Ang-II-induced AAA, but the cell type involved in the action of Cn in AAA formation remained unknown. Here, by employing newly created smooth muscle cell (SMC)-specific and endothelial cell (EC)-specific Cn-deficient mice (SM-Cn-/- and EC-Cn-/- mice), we show that Cn expressed in SMCs, but not ECs, was required for Ang-II-induced AAA. Unexpectedly, SMC Cn also played a structural role in the early onset and maintenance of Ang-II-induced hypertension, independently of its known phosphatase activity. Among the signaling pathways activated by Ang-II, Cn signaling is essential in SMCs, as nearly 90% of the genes regulated by Ang-II in the aorta required Cn expression in SMCs. Cn orchestrated, independently of its enzymatic activity, the induction by Ang-II of a transcriptional program closely related to SMC contractility and hypertension. Cn deletion in SMCs, but not its pharmacological inhibition, impaired the regulation of arterial contractility. Among the genes whose regulation by Ang-II required Cn expression but not its phosphatase activity, we discovered that Serpine1 was critical for Ang-II-induced hypertension. Indeed, pharmacological inhibition of PAI-1, the protein encoded by Serpine1, impaired SMCs contractility and readily regressed hypertension. Mechanistically, Serpine1 induction was mediated by Smad2 activation via the structural role of Cn. These findings uncover an unexpected role for Cn in vascular pathophysiology and highlight PAI-1 as a potential therapeutic target for hypertension.
Copyright: © 2025 Yunes-Leites et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract Blood vessels provide a versatile and adaptable transport system, but recent work has established that endothelial cells, which form the innermost lining of the vascular network, are also a source of molecular signals controlling the behavior of other cell types in the surrounding tissue. Pericytes are another essential component of the vessel wall, but comparably little is known about their signaling interactions with other cell populations during organ growth and patterning. Here, we have used tissue-specific and inducible mouse genetics, high-resolution imaging, single-cell RNA sequencing and cell culture experiments to address the function of three pericyte-derived growth factors in the postnatal development of two model organs, namely lung and brain. We found that Pdgfrb-CreERT2-controlled inactivation of the gene for hepatocyte growth factor (HGF) causes no overt alterations in the postnatal brain but impairs alveologenesis in the lung due to defective interaction with AT2 epithelial cells. Likewise, expression of brain-derived neurotrophic factor (BDNF) by pericytes is not required in the postnatal brain but controls lung development through interactions with the receptor tyrosine kinase TrkB in the pulmonary endothelium. Conversely, pericyte expression of the TGFβ family growth factor Nodal is not required for lung morphogenesis but regulates blood vessel growth and barrier function in the postnatal brain, which we attribute to signaling interactions with endothelial cells, astrocytes and microglia. Taken together, our findings establish that pericytes are a critical source of angiocrine signals that control morphogenetic processes in an organ-specific fashion.

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids and leukocytes within the arterial wall. By studying the aortic transcriptome of atherosclerosis-prone apolipoprotein E (ApoE-/-) mice, we aimed to identify novel players in the progression of atherosclerosis.
RNA-Seq analysis was performed on aortas from ApoE-/- and wild-type mice. AnxA8 expression was assessed in human and mice atherosclerotic tissue and healthy aorta. ApoE-/- mice lacking systemic AnxA8 (ApoE-/-AnxA8-/-) were generated to assess the effect of AnxA8 deficiency on atherosclerosis. Bone marrow transplantation (BMT) was also performed to generate ApoE-/- lacking AnxA8 specifically in bone marrow-derived cells. Endothelial-specific AnxA8 silencing in vivo was performed in ApoE-/- mice. The functional role of AnxA8 was analysed in cultured murine cells.
RNA-Seq unveiled AnxA8 as one of the most significantly upregulated genes in atherosclerotic aortas of ApoE-/- compared to wild-type mice. Moreover, AnxA8 was upregulated in human atherosclerotic plaques. Germline deletion of AnxA8 decreased the atherosclerotic burden, the size and volume of atherosclerotic plaques in the aortic root. Plaques of ApoE-/-AnxA8-/- were characterized by lower lipid and inflammatory content, smaller necrotic core, thicker fibrous cap and less apoptosis compared with those in ApoE-/-AnxA8+/+. BMT showed that hematopoietic AnxA8 deficiency had no effect on atherosclerotic progression. Oxidized low-density lipoprotein (ox-LDL) increased AnxA8 expression in murine aortic endothelial cells (MAECs). In vitro experiments revealed that AnxA8 deficiency in MAECs suppressed P/E-selectin and CD31 expression and secretion induced by ox-LDL with a concomitant reduction in platelet and leukocyte adhesion. Intravital microscopy confirmed the reduction in leukocyte and platelet adhesion in ApoE-/-AnxA8-/- mice. Finally, endothelial-specific silencing of AnxA8 decreased atherosclerosis progression.
Our findings demonstrate that AnxA8 promotes the progression of atherosclerosis by modulating endothelial-leukocyte interactions. Interventions capable of reducing AnxA8 expression in endothelial cells may delay atherosclerotic plaque progression.
This study shows that AnxA8 is upregulated in aorta of atheroprone mice and in human atherosclerotic plaques. Germline AnxA8 deficiency reduces platelet and leukocyte recruitment to activated endothelium as well as atherosclerotic burden, plaque size, and macrophage accumulation in mice. AnxA8 regulates oxLDL-induced adhesion molecules expression in aortic endothelial cells. Our data strongly suggest that AnxA8 promotes disease progression through regulation of adhesion and influx of immune cells to the intima. Endothelial specific silencing of AnxA8 reduced atherosclerosis progression. Therapeutic interventions to reduce AnxA8 expression may delay atherosclerosis progression.
© 2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.