Normalization of high-flow or removal of flow cannot stop high-flow induced endothelial proliferation

Abstract

Endothelial cells (ECs) are activated in response to high-fl ow. Our previous studies using arteriovenous fi stula (AVF) model have demonstrated that high-fl ow in blood vessels induces an early and rapid proliferation of ECs before arterial dilatation. Here, we investigated the proliferation of ECs, which had once been stimulated by high-fl ow loading, in a situation without the infl uence of high-fl ow. First, we induced high-fl ow in the rabbit common carotid artery by using AVF. Then, we removed the infl uence of high-fl ow by normalization of high-fl ow with the closure of AVF or by removal of fl ow itself with tissue isolation and organ culture or with cell culture of ECs, at the timing considered that ECs began to proliferate. Kinetics of ECs was investigated by a laser scanning confocal microscopy, phase-contrast microscopy and light microscopy using bromodeoxyuridine labeling method. We found that ECs, which had once been stimulated by high-flow, transiently proliferated even after normalization of high-fl ow or removal of fl ow. We assume that proliferation of ECs is promised when these cells start to proliferate after high-fl ow loading.Arteries are remodeled in response to a change of blood fl ow or wall shear stress (2, 5). Endothelial cells (ECs) are considered to detect the wall shear stress on the surface of themselves and play an important role in arterial remodeling (4). Our previous studies have demonstrated that high-flow induces the proliferation of arterial ECs before arterial dilatation in dogs, rats and rabbits by using arterio-venous fistula (AVF) model (5-9, 11, 12). This proliferation of ECs is the most distinct and earliest morphological change (5, 9), and is an initial change of the remodeling. However, mechanisms of the proliferation are still uncertain. In our high-flow model performed so far (5, 9), high-fl ow was continuing during the whole experimental period. Therefore, it is not certain whether continuous highflow is necessary during the whole period of the proliferation of ECs or only transient high-fl ow is required at the beginning of the proliferation of ECs. The purpose of this study is to investigate the proliferation of ECs, which have once been stimulated by high-fl ow loading, in a situation without the infl uence of high-fl ow. Here, we removed the infl uence of high-fl ow by 1) normalization of highflow with AVF closure, 2) removal of flow with isolation and organ culture of the artery or 3) with in vitro culture of ECs immediately after the timing considered that ECs began to proliferate. Kinetics of ECs was investigated by bromodeoxyuridine (BrdU) labeling (1,5,(8)(9)(10). We found that ECs once been stimulated by high-fl ow proliferated even after nor-

Epigenetic response of endothelial cells to different wall shear stress magnitudes: A report of new mechano‐miRNAs

“…We here show a pro-survival, proproliferation response of HWSS, given the results of gene expression analysis and the reported roles of the miRNAs upregulated under this condition. This is in-line with previous reports on the proliferative impact of HWSS on ECS (Yamauchi et al, 2005). This could also explain our previous report, in which a patient developed a daughter sac in a cerebral aneurysm followed over a course of several years (Sugiyama et al, 2016).…”

Analysis of arterial intimal hyperplasia: review and hypothesis

“…More recently, Thoma's hypothesis of the remodeling of normal intimal hyperplasia has been further investigated and subjected to experimental testing. It has been unequivocally confirmed in a number of elegant studies [ 159 - 173 ], leading to advanced modeling such as the Glagov and Kamiya-Togawa models. A very powerful conformation of the "slow flow" effects on expansion of hyperplasia and arterial narrowing was reported by Karino-Goldsmith group [ 174 - 181 ].…”

“…Richard Thoma was the first to enunciate a conceptually motivated approach to the problem. In my view, this was the foundation of his tremendous personal achievement in the field of arterial pathology, and for the extremely important observations and conclusions made by scientists whom his ideas inspired [ 159 - 161 , 163 - 173 , 181 - 184 , 187 , 188 ].…”

Neovascularization of coronary tunica intima (DIT) is the cause of coronary atherosclerosis. Lipoproteins invade coronary intima via neovascularization from adventitial vasa vasorum, but not from the arterial lumen: a hypothesis

“…Multiple observations have demonstrated that cells participating in this morphogenesis can be of different origins. As to regulations directing normal and pathological morphogenesis, a shear stress was suggested as the major factor [168-178]. In addition, I hypothesized that the arterial blood-tissue interface itself (as a topological entity) contributes to this morphogenesis, and the enhanced proliferative capacity of the arterial intima is a reflection of phenotype selection [69,179] (though these statements do not suggest mechanisms of regulation).…”