Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase

Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. infiltrating fibrocytes are major sources of arterial fibrosis in hypertension. Endothelial to mesenchymal transition likely also contributes, albeit to a lesser extent and pre-existing resident fibroblasts represent a minority of aortic collagen-producing cells in hypertension. This study shows that vascular stiffening represents a complex process involving recruitment and transformation of multiple cells types that ultimately elaborate adventitial extracellular matrix. strong class=”kwd-title” Keywords: Sca-1+ progenitors, endothelial to mesenchymal transition, circulating fibrocytes, Massons stain, adventitia and collagen deposition INTRODUCTION Hypertension induces a striking deposition of collagen in the aortic adventitia. This fibrotic process results in loss of the Windkessel function of the proximal aorta and worsens systolic hypertension and target organ damage. Increased pulse wave velocity, which reflects aortic stiffening, is associated with higher cardiovascular risk.1 Recently pulse forward wave amplitude, which likewise reflects aortic stiffness, was also found to associated with elevated risk of cardiovascular events.2 Resident fibroblasts have been traditionally been thought to be a major source of tissue fibrosis in wound Paradol healing, atherosclerosis and vascular fibrosis. We have previously shown that T cell cytokine IL-17A and increased mechanical stretch, which are commonly encountered in hypertension, drive expression of multiple collagen subtypes in primary mouse aortic fibroblasts. Paradol This is mediated by activation of the p38 MAP kinase and Paradol inhibition Paradol of this enzyme prevents collagen deposition both in vitro and in vivo.3 Hypertensive stimuli such as reactive oxygen species also activate fibroblasts, promoting fibrogenesis and tissue remodeling.4, 5 Stem cell antigen-1 (Sca-1, alternatively known as lymphocyte antigen 6 complex, locus A or Ly-6A) positive progenitor cells reside in the vascular adventitia which is a major site of collagen deposition in hypertension.3, 6 These pluripotent cells emerge during embryogenesis, persist into adulthood and represent roughly 20% of aortic adventitial cells.7, 8 In mouse aortas, they express several hematopoietic stem cell (HSC) markers, including Lin, c-kit and CD34.9, 10 Sca-1 cells are maintained by sonic hedgehog signaling (Shh) in the aortic adventitia, and in Shh?/? mice these cells are either absent or diminished in number.7 In healthy arteries of adult mice, Sca-1+ progenitors maintain endothelial and smooth muscles cells and generate vascular-like branching structures when cultured on matrigel.10 However, under disease conditions such as atherosclerosis and vascular injury, these cells have the capacity to differentiate into mesenchymal phenotype and might contribute to tissue fibrosis.8 Circulating fibrocytes are considered a specialized population of leukocytes that express collagen I and CD45.11C14 These cells migrate to inflamed or injured tissues via chemotactic ligand-receptor interactions, and have been shown to play a role in wound healing and fibrosis of the heart, Paradol lung and kidney.11C14 Once recruited to sites of inflammation, fibrocytes secrete additional chemokines that attract more fibrocytes and other leukocytes, including T cells, macrophages and dendritic cells.11, 15, 16 Fibrocytes also promote tissue remodeling by depositing fibrotic proteins including collagen. In addition, by secreting TGF-beta1, they may also induce transformation of endothelial cells to a fibroblast-like phenotype, a phenomenon known as endothelial to mesenchymal transition (EndoMT).11, 17 Thus, collagen-forming cells of the vessel can include resident fibroblasts, endothelial to mesenchymal transition, Sca-1 cells and recruitment of circulating fibrocytes. It is unclear however whether and how these different populations are involved the pathogenesis of Rabbit Polyclonal to SIRT3 aortic stiffening in hypertension. In the present study, we found that adventitial Sca-1+ progenitor cells acquire a collagen I-producing phenotype in hypertension, potentially contributing to collagen deposition and aortic.

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