Platelet Bone Morphogenetic Protein-4 Mediates Vascular Inflammation and Neointima Formation after Arterial Injury.
Marietta JankNikolaus von NiessenChristoph B OlivierHannah SchmittNathaly Anto-MichelIngo HilgendorfChristoph BodeMartin MoserJennifer S EsserQian ZhouPublished in: Cells (2021)
The purpose of this study is to investigate the role of platelet bone morphogenetic proteins (BMP)-4 during vascular inflammation and remodeling in a mouse model of carotid wire injury. Transgenic mice with a platelet-specific deletion of BMP-4 (BMP4Plt-/-) were generated. Intravital microscopy was performed to evaluate leukocyte adhesion to the vessel wall. Expression of adhesion molecules and chemokines were analyzed. Platelet-leukocyte aggregates (PLAs) were evaluated using flow cytometry. For carotid wire injury, BMP4Plt-/- mice were further crossed with LDLr-/- mice (BMP4Plt-/-/LDLr-/-) and fed with a high cholesterol diet for 2-weeks. Carotid wire injury was performed, and re-endothelialization and neointimal formation were evaluated. In comparison to the control mice, stimulation with TNFα resulted in fewer rolling and adherent leukocytes to the vessel wall in the BMP4Plt-/- mice. mRNA and protein expression of P-selectin and adhesion molecules were reduced in the aorta of the BMP4Plt-/- mice. In platelets from the BMP4Plt-/- mice, the expression of P-selectin was reduced, and fewer PLA formations were measured than in the control mice. Loss of platelet BMP-4 further prevented neointima formation after carotid wire injury. Endothelial regeneration after injury was decelerated in the BMP4Plt-/- mice, and confirmed in-vitro, where the deletion of platelet BMP-4 inhibited endothelial cell proliferation and migration. We demonstrate for the first time that platelet BMP-4 is involved during vascular inflammation and remodeling. This is partially mediated by the inhibition of platelet activation, reduced expression of adhesion molecules and inflammatory responses. Our findings identify platelet BMP-4 as a mediator of vascular inflammation in early atherosclerosis and restenosis.
Keyphrases
- mesenchymal stem cells
- bone regeneration
- high fat diet induced
- oxidative stress
- poor prognosis
- mouse model
- wild type
- cardiovascular disease
- rheumatoid arthritis
- peripheral blood
- insulin resistance
- bone marrow
- bone mineral density
- postmenopausal women
- coronary artery
- body composition
- pulmonary arterial hypertension
- vascular endothelial growth factor
- vascular smooth muscle cells