Dual Role of Thrombospondin-1 in Flow-Induced Remodeling.

Céline Grenier,Bertrand Toutain,Céline Fassot,Olivier Blanc-Brude,Antoine Caillon,Linda Grimaud,Mathilde Munier,Tristan Champin,Laurent Loufrani

doi:10.3390/ijms222112086

Abstract

(1) Background: Chronic increases in blood flow, as in cardiovascular diseases, induce outward arterial remodeling. Thrombospondin-1 (TSP-1) is known to interact with matrix proteins and immune cell-surface receptors, but its contribution to flow-mediated remodeling in the microcirculation remains unknown. (2) Methods: Mesenteric arteries were ligated in vivo to generate high- (HF) and normal-flow (NF) arteries in wild-type (WT) and TSP-1-deleted mice (TSP-1−/−). After 7 days, arteries were isolated and studied ex vivo. (3) Results: Chronic increases in blood flow induced outward remodeling in WT mice (increasing diameter from 221 ± 10 to 280 ± 10 µm with 75 mmHg intraluminal pressure) without significant effect in TSP-1−/− (296 ± 18 to 303 ± 14 µm), neutropenic or adoptive bone marrow transfer mice. Four days after ligature, pro inflammatory gene expression levels (CD68, Cox2, Gp91phox, p47phox and p22phox) increased in WT HF arteries but not in TSP-1−/− mice. Perivascular neutrophil accumulation at day 4 was significantly lower in TSP-1−/− than in WT mice. (4) Conclusions: TSP-1 origin is important; indeed, circulating TSP-1 participates in vasodilation, whereas both circulating and tissue TSP-1 are involved in arterial wall thickness and diameter expansion.

Highlights

Chronic changes in blood flow occur in physiological conditions such as exercise [1], pregnancy [2] or post-natal development and in pathological conditions such as arterial occlusive diseases [3], diabetes [4] or hypertension [5]
TSP-1 Modulates Flow-Mediated Remodeling In WT mice, the diameters of arteries submitted to a chronic increase in flow were greater than the diameters of control arteries under normal flow, NF (Figure 1a,c)
Circulating TSP-1 Induces Arterial Diameter Enlargement, but Tissue TSP-1 Participates in Arterial Parietal Thickening

Summary

Introduction

Chronic changes in blood flow occur in physiological conditions such as exercise [1], pregnancy [2] or post-natal development and in pathological conditions such as arterial occlusive diseases [3], diabetes [4] or hypertension [5]. Chronic increase in blood flow induces a remodeling of the arterial wall in order to adapt the wall strain to the new hemodynamic conditions, as described in large blood vessels [6] and small resistance arteries [7]. In large vessels (i.e., carotid arteries), chronic increase in blood flow induces limited vasodilatation [6] and parietal hypertrophy [8]. A chronic rise in blood flow triggers an increase in diameter associated with medial thickening [7]. The mechanism involved in vascular diameter adaptation is well described in large arteries, pathways implicated in arterial remodeling of resistance arteries are less described. Be expected due to dissimilar vascular wall constitution and specific local hemodynamic parameters

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