Histamine metabolism influences blood vessel branching in zebrafish reg6mutants

Cheng-Chen Huang,Chin-Wei Huang,Yih-Shyun E Cheng,John Yu

doi:10.1186/1471-213x-8-31

Abstract

BackgroundVascular branching morphogenesis is responsible for the extension of blood vessels into growing tissues, a process crucial for organogenesis. However, the genetic mechanism for vessel branching is largely unknown. Zebrafish reg6 is a temperature-sensitive mutation exhibiting defects in blood vessel branching which results in the formation of swollen vessel lumina during capillary plexus formation.ResultsWe performed a screening for chemical suppressors of reg6 and identified SKF91488, an inhibitor of histamine methyltransferase (HMT), that can rescue the reg6 vessel branching defects in a dose-dependent manner. Inhibition of HMT by SKF91488 presumably blocks histamine degradation, thus causing histamine accumulation. Consistent with this idea, we found that a high level of histamine also showed significant suppression of reg6 vessel phenotypes. Interestingly, when reg6 adults that had already developed swollen vessel lumina in regenerating fins were treated with histamine or SKF91488, either treatment significantly reduced the number of swollen vessels within 12 h, suggesting a rapid and constant influence of histamine on blood vessel branching. Furthermore, the expression of HMT was significantly elevated in reg6 regenerating fins. Conversely, lowering histamine by administering urocanic acid, a histidine decarboxylase inhibitor, enhanced the reg6 phenotypes. Finally, we identified that the transcription factor, egr-1 (early growth response factor 1), was closely associated with the reg6 phenotype and chemical treatments.ConclusionTaken together, our results suggest that blood vessel branching is influenced by histamine metabolism, possibly through regulating the expression of the egr-1 transcription factor.

Highlights

Vascular branching morphogenesis is responsible for the extension of blood vessels into growing tissues, a process crucial for organogenesis
Specific blood vessel branching defect of the zebrafish reg6 mutation The zebrafish reg6 mutation was isolated by its defects during caudal fin regeneration [17]
It was previously shown that the reg6 mutation causes blood vessel dilation during plexus formation of vessel regeneration due to defects in blood vessel branching, not in cell proliferation [16]

Summary

Introduction

Vascular branching morphogenesis is responsible for the extension of blood vessels into growing tissues, a process crucial for organogenesis. Blood vessels are important for transporting oxygen and nutrients to cells for survival and proper functioning. The pioneer trunk vessels, the dorsal aorta and cardinal vein, develop from vascular endothelial cells derived from the lateral plate mesoderm through a process called vasculogenesis. Blood vessels grow from existing vessels, through a process referred to as (page number not for citation purposes). In developing embryos, increasing evidence has revealed that blood vessels provide signals for the proper morphogenesis of developing organs [2]. In the adult form of organisms, angiogenesis and/or vasculogenesis to regrow blood vessels in wounded tissues is needed to repair damaged and replace lost tissues [3,4]. It has been well documented that angiogenesis plays a vital role in tumor growth, and the potential of antiangiogenesis drugs to inhibit tumor growth has been extensively explored worldwide [5]

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