Dataset Information

A comprehensive histopathological evaluation of vascular medial fibrosis: insights into the pathophysiology of arterial stiffening.

ABSTRACT: Medial vascular fibrosis contributes to arterial stiffening and reduced compliance, increasing the risk of cardiovascular events. We undertook the first comprehensive histopathologic study of medium-to-large caliber blood vessels (carotid, coronary, dorsalis pedis, internal mammary, iliac, mesenteric, pulmonary, and renal arteries) in 100 autopsy subjects to characterize medial fibrosis in relation to cardiovascular risk factors.Masson Trichrome staining of vascular tissue microarrays (TMAs) was digitally analyzed to determine the percent fibrosis (% collagen) of over 700 vascular segments. The percent fibrosis of the tunica media was strongly correlated within subjects across all systemic blood vessels (average r=0.53), suggesting that fibrosis is a global process independent of the predilection of the vessel towards the development of atherosclerosis. Hypertension, diabetes, age and poor renal function were significantly associated with increased systemic vascular fibrosis (p< or =0.03). By multivariable analysis, only poor renal function (p=0.003) was an independent predictor of higher levels of fibrosis. Finally, in a subset of 13 individuals we observed a significant correlation between pre-mortem pulse pressure and systemic vascular fibrosis (p<0.001).This study demonstrates that vascular fibrosis is a global process associated with diseases of aging and elevated pulse pressures.

SUBMITTER: Selvin E

PROVIDER: S-EPMC2813392 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A comprehensive histopathological evaluation of vascular medial fibrosis: insights into the pathophysiology of arterial stiffening.

Selvin Elizabeth E Najjar Samer S SS Cornish Toby C TC Halushka Marc K MK

Atherosclerosis 20090626 1

<h4>Objective</h4>Medial vascular fibrosis contributes to arterial stiffening and reduced compliance, increasing the risk of cardiovascular events. We undertook the first comprehensive histopathologic study of medium-to-large caliber blood vessels (carotid, coronary, dorsalis pedis, internal mammary, iliac, mesenteric, pulmonary, and renal arteries) in 100 autopsy subjects to characterize medial fibrosis in relation to cardiovascular risk factors.<h4>Methods and results</h4>Masson Trichrome stai ...[more]

PMID: 19632677

Similar Datasets

Project description:AimsElevation of arginase activity has been linked to vascular dysfunction in diabetes and hypertension by a mechanism involving decreased nitric oxide (NO) bioavailability due to L-arginine depletion. Excessive arginase activity also can drive L-arginine metabolism towards the production of ornithine, polyamines, and proline, promoting proliferation of vascular smooth muscle cells and collagen formation, leading to perivascular fibrosis. We hypothesized that there is a specific involvement of arginase 1 expression within the vascular endothelial cells in this pathology.Methods and resultsTo test this proposition, we used models of type 2 diabetes and metabolic syndrome. Studies were performed using wild type (WT), endothelial-specific arginase 1 knockout (EC-A1-/-) and littermate controls(A1con) mice fed high fat-high sucrose (HFHS) or normal diet (ND) for 6 months and isolated vessels exposed to palmitate-high glucose (PA/HG) media. Some WT mice or isolated vessels were treated with an arginase inhibitor, ABH [2-(S)-amino-6-boronohexanoic acid. In WT mice, the HFHS diet promoted increases in body weight, fasting blood glucose, and post-prandial insulin levels along with arterial stiffening and fibrosis, elevated blood pressure, decreased plasma levels of L-arginine, and elevated L-ornithine. The HFHS diet or PA/HG treatment also induced increases in vascular arginase activity along with oxidative stress, reduced vascular NO levels, and impaired endothelial-dependent vasorelaxation. All of these effects except obesity and hypercholesterolemia were prevented or significantly reduced by endothelial-specific deletion of arginase 1 or ABH treatment.ConclusionVascular dysfunctions in diet-induced obesity are prevented by deletion of arginase 1 in vascular endothelial cells or arginase inhibition. These findings indicate that upregulation of arginase 1 expression/activity in vascular endothelial cells has an integral role in diet-induced cardiovascular dysfunction and metabolic syndrome.

Project description:BackgroundArterial stiffness and wall shear stress are powerful determinants of cardiovascular health, and arterial stiffness is associated with increased cardiovascular mortality. Low and oscillatory wall shear stress, termed disturbed flow (d-flow), promotes atherosclerotic arterial remodeling, but the relationship between d-flow and arterial stiffness is not well understood. The objective of this study was to define the role of d-flow on arterial stiffening and discover the relevant signaling pathways by which d-flow stiffens arteries.MethodsD-flow was induced in the carotid arteries of young and old mice of both sexes. Arterial stiffness was quantified ex vivo with cylindrical biaxial mechanical testing and in vivo from duplex ultrasound and compared with unmanipulated carotid arteries from 80-week-old mice. Gene expression and pathway analysis was performed on endothelial cell-enriched RNA and validated by immunohistochemistry. In vitro testing of signaling pathways was performed under oscillatory and laminar wall shear stress conditions. Human arteries from regions of d-flow and stable flow were tested ex vivo to validate critical results from the animal model.ResultsD-flow induced arterial stiffening through collagen deposition after partial carotid ligation, and the degree of stiffening was similar to that of unmanipulated carotid arteries from 80-week-old mice. Intimal gene pathway analyses identified transforming growth factor-β pathways as having a prominent role in this stiffened arterial response, but this was attributable to thrombospondin-1 (TSP-1) stimulation of profibrotic genes and not changes to transforming growth factor-β. In vitro and in vivo testing under d-flow conditions identified a possible role for TSP-1 activation of transforming growth factor-β in the upregulation of these genes. TSP-1 knockout animals had significantly less arterial stiffening in response to d-flow than wild-type carotid arteries. Human arteries exposed to d-flow had similar increases TSP-1 and collagen gene expression as seen in our model.ConclusionsTSP-1 has a critical role in shear-mediated arterial stiffening that is mediated in part through TSP-1's activation of the profibrotic signaling pathways of transforming growth factor-β. Molecular targets in this pathway may lead to novel therapies to limit arterial stiffening and the progression of disease in arteries exposed to d-flow.

Dataset Information

A comprehensive histopathological evaluation of vascular medial fibrosis: insights into the pathophysiology of arterial stiffening.

Publications

A comprehensive histopathological evaluation of vascular medial fibrosis: insights into the pathophysiology of arterial stiffening.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets