Stefan Offermanns

The liver exhibits a marked regenerative capacity organized through distinct zones, yet how tissue mechanics coordinate zonated proliferation remains elusive. We reveal that mechanical cues critically contribute to mouse liver regeneration in a highly region-specific manner through sensing by a subpopulation of mid-lobular hepatocytes, which are characterized by dipeptidyl peptidase-4 (DPP4) expression and represent the key proliferative pool of hepatocytes. PIEZO1 is a primary mechanosensor enriched in zone 2 DPP4 ⁺ hepatocytes that integrates biomechanical cues to drive liver regrowth by insulin-like growth factor binding protein 2 (IGFBP2). Genetic disruption of PIEZO1 restrains hepatocyte proliferation and compromises liver regeneration, whereas zonated PIEZO1 gain of function enhances proliferation and accelerates recovery. These findings reveal that DPP4 ⁺ mechanosensitive hepatocytes orchestrate liver regrowth through PIEZO1-mediated mechanosensing, establishing a link between tissue mechanics and liver regeneration.

The neuropeptide neurotensin (NTS) is up-regulated in cardiac lymphatic endothelial cells (LECs) in response to ischemic or mechanical damage, but its role in cardiac remodeling is unknown. Here, we aimed to define the role of LEC-derived NTS in cardiac injury responses and to assess the therapeutic potential of targeting cardiac NTS signaling. In cultured murine and human cells, NTS reduced cardiomyocyte hypertrophy and fibroblast activation, and these effects were mediated by NTS receptor 2 (NTSR2)–dependent guanosine 3′,5′-monophosphate (cGMP) production. Consistent with an antihypertrophic and antifibrotic role of NTS, mice with LEC-specific Nts deletion exhibited aggravated hypertrophy and fibrosis after transverse aortic constriction (TAC) and myocardial infarction (MI). Similarly, cardiomyocyte-specific or activated fibroblast-specific inactivation of Ntsr2 led to enhanced cardiac remodeling after TAC. NTSR2 agonist NT150 reproduced the beneficial effects of NTS in cultured human and murine cells and ameliorated cardiac remodeling and dysfunction in both TAC and MI. Additionally, in freshly isolated cardiac tissues from patients with heart failure, NT150 induced cGMP production and suppressed prohypertrophic signaling. These findings identify NTS as an endogenous inhibitor of adverse cardiac remodeling and suggest NTSR2 agonism as a therapeutic strategy in heart failure.

Background: Atherosclerosis is a chronic inflammatory vascular disorder with persistent residual inflammation even after standard lipid-lowering therapy. Mounting evidence from bench to bedside suggests that diabetes and obesity accelerate atherosclerosis development. Tirzepatide (TZP), a dual Glucagon-Like Peptide-1 Receptor/Glucose-Dependent Insulinotropic Polypeptide Receptor (GLP-1R/GIPR) agonist approved for treating diabetes and obesity, has demonstrated proven cardiometabolic efficacy in large cardiovascular outcome trials. However, it remains largely uncertain whether TZP attenuates atherosclerosis independent of its anti-diabetic and anti-obese effects through direct actions on the vasculature. Methods: We established atherosclerotic mouse models under diabetic, obese, and non-diabetic/non-obese conditions. Analysis of covariance (ANCOVA) and pair-feeding experiments were applied to experimentally decouple weight-dependent metabolic improvement from intrinsic vasculoprotection. Molecular and cell biological assays in human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs) were performed to dissect the underlying signaling mechanisms. Results: TZP markedly reduced aortic plaque burden and inflammation, restrained necrotic core enlargement, and improved plaque stability across all experimental mouse models. Both ANCOVA and pair-feeding experiments confirmed that these atheroprotective effects were independent of food intake and body weight loss. Furthermore, TZP attenuated systemic and vascular inflammation in Tumor Necrosis Factor-α (TNF)-treated C57BL/6J mice, and this protection occurred without changes in body weight or blood glucose levels. Mechanistically, TZP directly targeted endothelial cells and activated the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/endothelial nitric oxide synthase (eNOS) pathway, increased eNOS phosphorylation and nitric oxide bioavailability, consequently downregulating the expression of the pro-inflammatory adhesion molecules Vascular Cell Adhesion Molecule-1 (VCAM–1) and Intercellular Adhesion Molecule-1 (ICAM–1). Conclusions: TZP arrests atherosclerosis progression through weight loss-independent anti-inflammatory mechanisms. These findings implicate TZP as a promising therapeutic drug for mitigating residual vascular inflammation in patients with atherosclerotic cardiovascular disease (ASCVD), irrespective of glycemic status or obesity. Clinical Perspective: What Is New?: Tirzepatide exerts direct anti-atherosclerotic effects in preclinical mouse models of atherosclerosis under diabetic, obese, and non-obese conditions. Tirzepatide directly targets endothelial GLP-1R/GIPR and downstream cAMP/PKA/eNOS signaling pathway to suppress NF-κB-driven vascular inflammation, thereby uncovering a previously unrecognized vasculoprotective mechanism underlying its cardiovascular benefits What Are the Clinical Implications?: Tirzepatide exerts direct vascular protective effects independent of body weight reduction, suggesting that its cardiovascular benefits may extend beyond glycemic control and obesity management. Tirzepatide may represent a promising therapeutic drug for addressing residual vascular inflammation in ASCVD patients, including those without overt diabetes or obesity

BACKGROUND: Atherosclerotic cardiovascular disease remains the leading cause of death worldwide. Most current pharmacotherapies target conventional risk factors that promote atherosclerosis rather than intrinsic resilience factors that protect atherosclerosis in the face of risk factors. Here, we investigated the role of desert hedgehog (DHH), a canonical ligand of the hedgehog signaling pathway, as a novel resilience factor that restrains endothelial mesenchymal transition (EndoMT) and protects against atherosclerosis. METHODS: scRNA-seq was performed on atheroprone and atheroprotective regions of the ApoE knockout mouse aorta to identify mechanoresponsive genes associated with atherosclerosis. Endothelial cell-specific Dhh knockout mice were subjected to partial carotid ligation and hypercholesterolemic conditions to investigate the role of endothelial Dhh in atherosclerosis progression. scRNA-seq, bulk RNA sequencing, endothelial lineage tracing, immunoprecipitation-coupled mass spectrometry, and surface plasmon resonance were used to investigate the role and mechanism of DHH in EndoMT. RESULTS: DHH protein expression was enriched in arterial endothelium from mice, porcine, and humans. However, DHH expression was significantly reduced in atherosclerotic arteries and serum from patients with coronary artery disease. scRNA-seq of atheroprone and atheroresistant region of mouse aorta identified Dhh as a novel mechanoresponsive gene enriched in aortic regions exposed to unidirectional laminar flow. Endothelial cell-specific Dhh knockout (DhhecKO) mice exhibited increased atherosclerotic lesion area, large necrotic cores, and reduced collagen content following partial carotid ligation. Similarly, under hypercholesterolemic conditions, both male and female DhhecKO mice showed aggravated atherosclerosis progression. scRNA-seq of DhhecKO mouse aortas revealed an increased proportion of endothelial cells undergoing mesenchymal transition, indicating enhanced EndoMT. These findings were corroborated by bulk RNA-sequencing of DHH depleted HUVECs and endothelial lineage tracing in inducible DhhecKO mice. Mechanistically, DHH directly interacted with PAI-1 and suppressed PAI 1 induced EndoMT. PAI 1 promoted EndoMT in ECs through activation of canonical TGF-? signaling and noncanonical AKT/ERK1/2 signaling via interaction with LRP1. Neutralization of PAI 1 or inhibition of LRP1, AKT/ERK1/2, or SMAD3 signaling abolished DHH deficiency-induced EndoMT. DHH competitively inhibited PAI-1 binding to LRP1, thereby attenuating downstream pro-EndoMT signaling. Intriguingly, treatment with PAI-1 inhibitor TM5275 mitigated endothelial Dhh deficiency induced EndoMT in vivo. Of translational relevance, recombinant mouse DHH protein administration reduced atherosclerosis progression, stabilized plaque, and decreased the expression of EndoMT markers in ApoE knockout mice. CONCLUSIONS: DHH is an intrinsic endothelial cell-enriched resilience factor that protects against EndoMT and atherosclerosis by preventing PAI-1 signaling. The present study implicates endothelial DHH as a potential therapeutic target for atherosclerotic cardiovascular disease.

Amyloid precursor protein (APP) gives rise to amyloid-β, a pathological factor in Alzheimer’s disease. However, the physiological role of APP and its homolog amyloid precursor–like protein 2 (APLP2), which are also widely expressed outside the nervous system, is largely unknown. Here, we show that endothelial APP and APLP2 are required for postischemia angiogenesis after myocardial infarction (MI). We found that hypoxia induced the endothelial expression of α-secretases, resulting in nonamyloidogenic processing of APP and APLP2 into the soluble forms APPsα and APLP2sα. Loss of endothelial APP and APLP2 led to decreased neovascularization as well as increased heart failure and mortality after MI, a phenotype that could be rescued by endothelial expression of APPsα. APPsα and APLP2sα exerted their proangiogenic effect by positive allosteric modulation of the endothelial receptor tyrosine kinase KIT, which promotes postischemia neovascularization. Our data identify a function of APP and APLP2 in endothelial cells, which is required for postischemia tissue repair, and suggest approaches to improve regeneration after MI and other ischemic diseases.

Insulin resistance is the biological phenomenon in which the human body's normal response to the metabolic hormone insulin is compromised. Insulin is a regulator of most of the essential metabolic steps in the body that control energy homoeostasis, so dysregulation leads to multiple diverse human diseases including, most prominently, Type 2 diabetes mellitus. Insulin resistance also leads to the development of a metabolic profile that is strongly atherogenic, thus accelerating the initiation and development of atherosclerosis and its cardiovascular disease consequences, namely heart attacks, strokes and limb amputations. More recently, insulin resistance has been recognised as a contributing factor and therapeutic target for an increasing number of diverse diseases. Insulin acts in the established ligand‐receptor manner of activating a tyrosine kinase receptor, which mediates multiple forms of well‐characterised downstream signalling, ultimately leading to a serine/threonine kinase cascade, resulting in the phosphorylation of transcription factors and the regulation of gene expression in normal physiology. Although it was originally suspected that insulin resistance was a result of aberrant insulin signalling, resulting from the action of an unspecified lipophilic metabolite, no such factor has been identified in the last several decades. However, modern research has identified a range of traditional and novel factors which modulate insulin resistance and hence pathophysiology. In this review, it is speculated that there may be multiple forms of insulin resistance, each susceptible to an individual therapeutic approach, and also potentially idiosyncratic insulin resistance requiring empirical therapies. Further research is required to develop therapies for the factors so far discovered and to continue to search for other factors that are also potentially vulnerable to therapeutic targeting. Insulin resistance remains a prominent factor compromising human health, and ongoing research is required to understand the aetiology and lessen the impact of this condition.