Imatinib Sets Pericyte Mosaic in the Retina.

Tamás Kovács-Öller,Botir T Sagdullaev,Béla Völgyi,Elena Ivanova,Ádám J Tengölics,Gergely Szarka

doi:10.3390/ijms21072522

Abstract

The nervous system demands an adequate oxygen and metabolite exchange, making pericytes (PCs), the only vasoactive cells on the capillaries, essential to neural function. Loss of PCs is a hallmark of multiple diseases, including diabetes, Alzheimer’s, amyotrophic lateral sclerosis (ALS) and Parkinson’s. Platelet-derived growth factor receptors (PDGFRs) have been shown to be critical to PC function and survival. However, how PDGFR-mediated PC activity affects vascular homeostasis is not fully understood. Here, we tested the hypothesis that imatinib, a chemotherapeutic agent and a potent PDGFR inhibitor, alters PC distribution and thus induces vascular atrophy. We performed a morphometric analysis of the vascular elements in sham control and imatinib-treated NG2-DsRed mice. Vascular morphology and the integrity of the blood–retina barrier (BRB) were evaluated using blood albumin labeling. We found that imatinib decreased the number of PCs and blood vessel (BV) coverage in all retinal vascular layers; this was accompanied by a shrinkage of BV diameters. Surprisingly, the total length of capillaries was not altered, suggesting a preferential effect of imatinib on PCs. Furthermore, blood–retina barrier disruption was not evident. In conclusion, our data suggest that imatinib could help in treating neurovascular diseases and serve as a model for PC loss, without BRB disruption.

Highlights

Platelet-derived growth factor receptor beta (PDGFR-β) is amongst the major markers expressed by pericytes (PCs) found on the capillaries and is responsible for metabolism and oxygen supply
Imatinib treatment acts on PCs in the adult retina, and, a decrease in PC number accompanied by a decrease of vascular density and interference with neurovascular unit (NVU) (Figure 1c) function is expected, leading to various forms of retinal pathologies
As a potent Platelet-derived growth factor receptors (PDGFRs), tyrosine kinase and KIT inhibitor has been successfully used in treating cancer, and could provide an alternative treatment strategy in neurovascular diseases

Summary

Introduction

Platelet-derived growth factor receptor beta (PDGFR-β) is amongst the major markers expressed by pericytes (PCs) found on the capillaries and is responsible for metabolism and oxygen supply. Together with the PDGF-BB ligand, it promotes vascular maturation and stabilization by recruiting PCs and their progenitors [1,2] Their role has been controversial for a long time [3], it is clear that PCs are able to regulate blood flow in the nervous tissue as part of the neurovascular unit (NVU) (Figure 1c) [4,5,6,7,8]. They express alpha-smooth muscle actin, making them capable of active vasoconstriction [9], as previously functionally shown by Ivanova et al, 2017 [6]. PCs regulate the blood–brain barrier (BBB) in development [17,18] while in the adult CNS, PC-deficient BVs become dilated without BBB impairment [19,20]

Methods

Results

Conclusion