Noncaloric monosaccharides induce excessive sprouting angiogenesis in zebrafish via foxo1a-marcksl1a signal

Reviewer #1 (Public Review):

Summary:

This manuscript successfully established a new short-term model of diabetic retinopathy by treating zebrafish embryos with high concentrations of monosaccharides, resembling the hyperangiogenic characteristics observed in proliferative diabetic retinopathy in patients. They found that excessive angiogenesis induced by glucose and noncaloric monosaccharides was achieved by activating the quiescent endothelial cells into proliferating tip cells. Importantly, the authors further confirmed the effects of monosaccharides on inducing excessive angiogenesis were mediated by the foxo1a-marcksl1a pathway.

Strengths:

These results showed the potentially detrimental effects of the noncaloric monosaccharides on blood vessel function and provided novel insights into the underlying mechanisms.

Weaknesses:

The mechanism of noncaloric monosaccharides inducing excessive sprouting angiogenesis is not solid enough.

Reviewer #2 (Public Review):

In the manuscript entitled "Noncaloric monosaccharides induce excessive sprouting angiogenesis in zebrafish via foxo1a-marcksl1a signal". Liu et al. observed that glucose and noncaloric monosaccharides can prompt an excessive formation of blood vessels, particularly intersegmental vessels (ISVs). They propose that these branched vessels arise from the ectopic activation of quiescent endothelial cells (ECs) into tip cells. Moreover, through single-cell transcriptome sequencing analysis of embryonic endothelial cells exposed to glucose, they noted an increased proportion of arterial and capillary endothelial cells, proliferative endothelial cells, along with a series of upregulated genes in categories of blood vessel morphogenesis, development, and pro-angiogenesis. The authors provide evidence suggesting that caloric and noncaloric monosaccharides (NMS) induce excessive angiogenesis via the foxo1a-Marcksl1a pathway.

The authors address an important problem about the effects of artificially sweetened beverages such as noncaloric monosaccharides on blood vessels. However, the study lacks adequate experimental data and comprehensive analyses to support the mechanistic conclusions, which require extensive revisions.

Reviewer #3 (Public Review):

The authors have investigated the effect of noncaloric monosaccharides on angiogenesis in the zebrafish embryo. These compounds are used as substitutes of sugars to sweeten beverages and they are commonly used by diabetic patients. The authors show that noncaloric monosaccharides and glucose similarly induce excessive blood vessel formation due to the increased formation of tip cells by endothelial cells. The authors show that this excessive angiogenesis involved the foxo1a-marcksl1a pathway.

A limitation of the study is that the mechanism of angiogenesis in the retinal circulation and in peripheral vasculature is certainly different.

This result suggests that these noncaloric monosaccharides share common side effects with glucose. Consequently, more caution should be taken with regard to the use of these artificial sweeteners. This work is of interest for better management of diabetes.