Oligonucleotide Microarrays Identified Potential Regulatory Genes Related to Early Outward Arterial Remodeling Induced by Tissue Plasminogen Activator.

Olga Plekhanova,Irina Beloglazova,Bradford C Berk,Vsevolod Tkachuk,Yelena Parfyonova

doi:10.3389/fphys.2019.00493

Abstract

Constrictive vascular remodeling limiting blood flow, as well as compensatory outward remodeling, has been observed in many cardiovascular diseases; however, the underlying mechanisms regulating the remodeling response of the vessels remain unclear. Plasminogen activators (PA) are involved in many of the processes of vascular remodeling. We have shown previously that increased levels of tissue-type PA (tPA) contributes to outward vascular remodeling. To elucidate the mechanisms involved in the induction of outward remodeling we characterized changes in the expression profiles of 8799 genes in injured rat carotid arteries 1 and 4 days after recombinant tPA treatment compared to vehicle. Periadventitial tPA significantly increased lumen size and vessel area, encompassed by the external elastic lamina, at both one and 4 days after treatment. Among 41 differentially expressed known genes 1 day after tPA application, five genes were involved in gene transcription, five genes were related to the regulation of vascular tone [for example, thromboxane A2 receptor (D32080) or non-selective-type endothelin receptor (S65355)], and eight genes were identified as participating in vascular innervation [for example, calpain (D14478) or neural cell adhesion molecule L1 (X59149)]. Four days after injury in tPA-treated arteries, four genes, regulating vascular tone, were differentially expressed. Thus, tPA promotes outward arterial remodeling after injury, at least in part, by regulating expression of genes in the vessel wall related to function of the nervous system and vascular tone.

Highlights

Vascular remodeling is one of the most important mechanisms responsible for lumen narrowing in many cardiovascular pathologies (Paneni et al, 2017)
To assess the role of gene expression changes in early processes leading to the outward vascular remodeling induced by type PA (tPA), we investigated alterations in gene expression profiles of rat common carotids after injury and local treatment with the recombinant tPA
To assess tPA influence on the injured artery remodeling, we measured the area of lumen, the area, encompassed by the external elastic lamina (EEL), and intima-plus-media area [termed intima-media thickness (IMT)]; main parameters reflecting vessel remodeling

Summary

Introduction

Vascular remodeling is one of the most important mechanisms responsible for lumen narrowing in many cardiovascular pathologies (Paneni et al, 2017). Inward arterial remodeling is associated with high cardiovascular mortality, while outward vascular remodeling is considered to be a positive compensatory mechanism that provides adequate blood flow (van Varik et al, 2012). We have tPA and Outward Vascular Remodeling demonstrated previously that tissue-type plasminogen activator (tPA) attenuated inward arterial remodeling (Parfyonova et al, 2004). Despite the active interest of many research groups to the problem of regulation of arterial remodeling, highly effective mechanisms are still to be found (Goel et al, 2012). There are contradictory data about the influence of tPA; it contributes to cell proliferation, and in the previous study, tPA reduced neointima formation (Parfyonova et al, 2004)

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