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Noncaloric Monosaccharides Induce Excessive Sprouting Angiogenesis in Zebrafish via the Foxo1a-Marcksl1a Signaling Pathway


Core Concepts
Noncaloric monosaccharides, including L-glucose and mannose, induce excessive sprouting angiogenesis in zebrafish embryos through the downregulation of Foxo1a, which leads to the upregulation of its target gene Marcksl1a.
Abstract
The study established a short-term zebrafish model that exhibits significant excessive angiogenesis, resembling the hyperangiogenic characteristics observed in proliferative diabetic retinopathy (PDR) induced by high glucose treatment. Using this model, the researchers examined the effects of noncaloric monosaccharides on blood vessel development and investigated the underlying molecular mechanisms. Key highlights: Glucose and noncaloric monosaccharides, including L-glucose, fructose, mannose, ribose, and arabinose, could induce excessive formation of blood vessels, especially intersegmental vessels (ISVs), in zebrafish embryos. The excessive angiogenesis was caused by the ectopic activation of quiescent endothelial cells (ECs) into tip cells. Single-cell transcriptomic sequencing analysis revealed an increased ratio of tip cells and proliferating ECs, accompanied by the downregulation of the transcription factor Foxo1a in the ECs of glucose-treated embryos. Further experiments validated that Foxo1a negatively regulated the expression of its target gene Marcksl1a, and the downregulation of Foxo1a-Marcksl1a signaling pathway mediated the excessive angiogenesis induced by both caloric and noncaloric monosaccharides. The findings suggest that the consumption of noncaloric monosaccharides may not be a suitable alternative to sugar-sweetened beverages, as they can also induce vascular dysfunction, potentially contributing to the development of diabetic complications.
Stats
Glucose concentration in the embryos treated with high glucose was significantly higher than that in the control group. The total length of intersegmental vessels (ISVs) was significantly increased in the glucose-treated embryos compared to the control. The ratio of arterial and capillary ECs and proliferating ECs was increased in the high glucose-treated embryos.
Quotes
"Artificially sweetened beverages containing noncaloric monosaccharides were suggested as healthier alternatives to sugar-sweetened beverages. Nevertheless, the potential detrimental effects of these noncaloric monosaccharides on blood vessel function remain inadequately understood." "Our results provided new evidence for the negative roles of caloric and noncaloric monosaccharides on vascular development."

Deeper Inquiries

How do the effects of noncaloric monosaccharides on vascular development compare to those of other sugar substitutes, such as sugar alcohols or artificial sweeteners?

Noncaloric monosaccharides, such as glucose and fructose, have been shown to induce excessive angiogenesis in zebrafish embryos, leading to the formation of abnormal blood vessels. This excessive angiogenesis is characterized by the ectopic activation of quiescent endothelial cells into tip cells, resulting in the sprouting of new blood vessels. In contrast, other sugar substitutes like sugar alcohols (sorbitol, mannitol, etc.) and artificial sweeteners do not seem to induce similar effects on vascular development. In the study, it was observed that noncaloric monosaccharides, including L-glucose, D-mannose, D-ribose, and L-arabinose, could all induce excessive angiogenesis, while disaccharides like lactose, maltose, and sucrose did not cause significant abnormal vessel formation. This suggests that the effects of noncaloric monosaccharides on vascular development are distinct from those of other sugar substitutes, indicating a specific mechanism through which noncaloric monosaccharides impact angiogenesis.

What are the potential long-term consequences of excessive angiogenesis induced by noncaloric monosaccharides, and how might they contribute to the development of diabetic complications?

Excessive angiogenesis induced by noncaloric monosaccharides can have significant long-term consequences on vascular health and contribute to the development of diabetic complications. In conditions like proliferative diabetic retinopathy (PDR), characterized by abnormal blood vessel growth in the retina, excessive angiogenesis can lead to vascular dysfunction and impaired blood flow regulation. This can result in complications such as retinopathy, nephropathy, neuropathy, and cardiovascular diseases, which are common in individuals with diabetes. The ectopic activation of quiescent endothelial cells into tip cells, as observed in the study, can disrupt the normal vascular architecture and function, leading to the formation of immature and leaky blood vessels. These abnormal vessels are prone to hemorrhage, edema, and impaired tissue perfusion, which can further exacerbate diabetic complications. Additionally, the upregulation of proangiogenic genes and the altered balance of endothelial cell subpopulations induced by noncaloric monosaccharides can perpetuate the pathological angiogenesis and contribute to the progression of diabetic vascular complications over time.

Given the conserved nature of the Foxo1a-Marcksl1a signaling pathway, could similar mechanisms be involved in the vascular dysfunction observed in other metabolic disorders or age-related diseases?

The Foxo1a-Marcksl1a signaling pathway identified in the study as a key regulator of excessive angiogenesis induced by noncaloric monosaccharides is known to play crucial roles in vascular development and homeostasis. The conserved nature of this pathway suggests that similar mechanisms could be involved in vascular dysfunction observed in other metabolic disorders or age-related diseases. In conditions like atherosclerosis, hypertension, and metabolic syndrome, dysregulation of Foxo1a and its downstream targets like Marcksl1a could contribute to endothelial dysfunction, impaired angiogenesis, and vascular remodeling. The imbalance between proangiogenic and antiangiogenic factors controlled by Foxo1a may lead to aberrant blood vessel formation and compromised vascular integrity, which are common features of various vascular diseases. Moreover, in age-related diseases like age-related macular degeneration (AMD) or vascular dementia, alterations in the Foxo1a-Marcksl1a pathway could impact vascular function and contribute to disease pathogenesis. The involvement of this signaling pathway in regulating endothelial cell behavior and angiogenic processes suggests its potential relevance in a broader spectrum of vascular-related disorders beyond diabetes.
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