-
Cardiovascular Research Jul 2023Cardiovascular disease (CVD) is a serious health challenge, causing more deaths worldwide than cancer. The vascular endothelium, which forms the inner lining of blood... (Review)
Review
Cardiovascular disease (CVD) is a serious health challenge, causing more deaths worldwide than cancer. The vascular endothelium, which forms the inner lining of blood vessels, plays a central role in maintaining vascular integrity and homeostasis and is in direct contact with the blood flow. Research over the past century has shown that mechanical perturbations of the vascular wall contribute to the formation and progression of atherosclerosis. While the straight part of the artery is exposed to sustained laminar flow and physiological high shear stress, flow near branch points or in curved vessels can exhibit 'disturbed' flow. Clinical studies as well as carefully controlled in vitro analyses have confirmed that these regions of disturbed flow, which can include low shear stress, recirculation, oscillation, or lateral flow, are preferential sites of atherosclerotic lesion formation. Because of their critical role in blood flow homeostasis, vascular endothelial cells (ECs) have mechanosensory mechanisms that allow them to react rapidly to changes in mechanical forces, and to execute context-specific adaptive responses to modulate EC functions. This review summarizes the current understanding of endothelial mechanobiology, which can guide the identification of new therapeutic targets to slow or reverse the progression of atherosclerosis.
Topics: Humans; Endothelial Cells; Atherosclerosis; Endothelium, Vascular; Hemodynamics; Cardiovascular Diseases; Stress, Mechanical; Mechanotransduction, Cellular
PubMed: 37163659
DOI: 10.1093/cvr/cvad076 -
Cell Reports May 2023Crosstalk between cardiac cells is critical for heart performance. Here we show that vascular cells within human cardiac organoids (hCOs) enhance their maturation, force...
Crosstalk between cardiac cells is critical for heart performance. Here we show that vascular cells within human cardiac organoids (hCOs) enhance their maturation, force of contraction, and utility in disease modeling. Herein we optimize our protocol to generate vascular populations in addition to epicardial, fibroblast, and cardiomyocyte cells that self-organize into in-vivo-like structures in hCOs. We identify mechanisms of communication between endothelial cells, pericytes, fibroblasts, and cardiomyocytes that ultimately contribute to cardiac organoid maturation. In particular, (1) endothelial-derived LAMA5 regulates expression of mature sarcomeric proteins and contractility, and (2) paracrine platelet-derived growth factor receptor β (PDGFRβ) signaling from vascular cells upregulates matrix deposition to augment hCO contractile force. Finally, we demonstrate that vascular cells determine the magnitude of diastolic dysfunction caused by inflammatory factors and identify a paracrine role of endothelin driving dysfunction. Together this study highlights the importance and role of vascular cells in organoid models.
Topics: Humans; Endothelial Cells; Myocytes, Cardiac; Pericytes; Signal Transduction; Organoids
PubMed: 37105170
DOI: 10.1016/j.celrep.2023.112322 -
The Journal of Clinical Investigation Aug 2023Neutrophil (PMN) mobilization to sites of insult is critical for host defense and requires transendothelial migration (TEM). TEM involves several well-studied sequential...
Neutrophil (PMN) mobilization to sites of insult is critical for host defense and requires transendothelial migration (TEM). TEM involves several well-studied sequential adhesive interactions with vascular endothelial cells (ECs); however, what initiates or terminates this process is not well-understood. Here, we describe what we believe to be a new mechanism where vessel-associated macrophages through localized interactions primed EC responses to form ICAM-1 "hot spots" to support PMN TEM. Using real-time intravital microscopy of LPS-inflamed intestines in CX3CR1-EGFP macrophage-reporter mice, complemented by whole-mount tissue imaging and flow cytometry, we found that macrophage vessel association is critical for the initiation of PMN-EC adhesive interactions, PMN TEM, and subsequent accumulation in the intestinal mucosa. Anti-colony stimulating factor 1 receptor Ab-mediated macrophage depletion in the lamina propria and at the vessel wall resulted in elimination of ICAM-1 hot spots impeding PMN-EC interactions and TEM. Mechanistically, the use of human clinical specimens, TNF-α-KO macrophage chimeras, TNF-α/TNF receptor (TNF-α/TNFR) neutralization, and multicellular macrophage-EC-PMN cocultures revealed that macrophage-derived TNF-α and EC TNFR2 axis mediated this regulatory mechanism and was required for PMN TEM. As such, our findings identified clinically relevant mechanisms by which macrophages regulate PMN trafficking in inflamed mucosa.
Topics: Humans; Mice; Animals; Endothelial Cells; Intercellular Adhesion Molecule-1; Tumor Necrosis Factor-alpha; Cell Adhesion; Neutrophil Infiltration; Cells, Cultured; Intestinal Mucosa; Neutrophils; Macrophages; Endothelium, Vascular
PubMed: 37261911
DOI: 10.1172/JCI170733 -
The Journal of Clinical Investigation Aug 2023The pulmonary vasculature has been frequently overlooked in acute and chronic lung diseases, such as acute respiratory distress syndrome (ARDS), pulmonary fibrosis (PF),... (Review)
Review
The pulmonary vasculature has been frequently overlooked in acute and chronic lung diseases, such as acute respiratory distress syndrome (ARDS), pulmonary fibrosis (PF), and chronic obstructive pulmonary disease (COPD). The primary emphasis in the management of these parenchymal disorders has largely revolved around the injury and aberrant repair of epithelial cells. However, there is increasing evidence that the vascular endothelium plays an active role in the development of acute and chronic lung diseases. The endothelial cell network in the capillary bed and the arterial and venous vessels provides a metabolically highly active barrier that controls the migration of immune cells, regulates vascular tone and permeability, and participates in the remodeling processes. Phenotypically and functionally altered endothelial cells, and remodeled vessels, can be found in acute and chronic lung diseases, although to different degrees, likely because of disease-specific mechanisms. Since vascular remodeling is associated with pulmonary hypertension, which worsens patient outcomes and survival, it is crucial to understand the underlying vascular alterations. In this Review, we describe the current knowledge regarding the role of the pulmonary vasculature in the development and progression of ARDS, PF, and COPD; we also outline future research directions with the hope of facilitating the development of mechanism-based therapies.
Topics: Humans; Lung; Endothelial Cells; Pulmonary Disease, Chronic Obstructive; Respiratory Distress Syndrome; Pulmonary Fibrosis; Endothelium, Vascular
PubMed: 37581311
DOI: 10.1172/JCI170502 -
Nature Communications Sep 2023The decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular...
The decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular endothelial cells (VECs) remain unclear. Here, we identify a crucial role for CD44, a multifunctional adhesion molecule, in controlling autophagy and ageing in VECs. The CD44 intercellular domain (CD44ICD) negatively regulates autophagy by reducing PIK3R4 and PIK3C3 levels and disrupting STAT3-dependent PtdIns3K complexes. CD44 and its homologue clec-31 are increased in ageing vascular endothelium and Caenorhabditis elegans, respectively, suggesting that an age-dependent increase in CD44 induces autophagy decline and ageing phenotypes. Accordingly, CD44 knockdown ameliorates age-associated phenotypes in VECs. The endothelium-specific CD44ICD knock-in mouse is shorter-lived, with VECs exhibiting obvious premature ageing characteristics associated with decreased basal autophagy. Autophagy activation suppresses the premature ageing of human and mouse VECs overexpressing CD44ICD, function conserved in the CD44 homologue clec-31 in C. elegans. Our work describes a mechanism coordinated by CD44 function bridging autophagy decline and ageing.
Topics: Humans; Animals; Mice; Endothelium, Vascular; Endothelial Cells; Caenorhabditis elegans; Aging; Aging, Premature; Autophagy; Hyaluronan Receptors
PubMed: 37684253
DOI: 10.1038/s41467-023-41346-y