
Neuropilin-1 expression in perivascular cells acts as a tissue-specific modifier of endothelial VEGFA/VEGFR2 signaling and vascular leakage.


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Neuropilin-1 (NRP1) regulates endothelial cell (EC) biology through modulating vascular endothelial growth factor receptor 2 (VEGFR2) signalling by presenting VEGFA. How NRP1 impacts VEGFA-mediated vascular hyperpermeability however is unresolved, being described as having a positive or passive function. Using EC-specific Nrp1 knock-out mice, we discover that EC-expressed NRP1 exerts an organotypic role. In ear skin, VEGFA/VEGFR2-mediated vascular leakage increased following EC NRP1 knock-out, showing that NRP1 negatively regulates VEGFR2 signalling. Conversely, in back skin and trachea, EC NRP1 knock-out decreased vascular leakage. Accordingly, VE-cadherin phosphorylation increased in the ear skin but was suppressed in back skin of Nrp1 iECKO mice. NRP1 has been shown to have the ability to act in a juxtacrine manner. Importantly, NRP1 was more abundant in perivascular cells of the ear skin than back skin. Global NRP1 knock-out suppressed VEGFA-induced vascular leakage in the ear skin, implicating perivascular NRP1 as a juxtacrine co-receptor of VEGFA in this compartment. Altogether, we demonstrate that perivascular NRP1 is an active participant in EC VEGFA/VEGFR2 signalling and acts as an organotypic modifier of EC biology.

### Competing Interest Statement

The authors have declared no competing interest.

Neuropilin-1 controls vascular permeability through juxtacrine regulation of endothelial adherens junctions

neuropilin-1-modulates-vascular-permeability-through-juxtacrine-regulation-of-endothelial-adherens-junctions


Neuropilin-1 Modulates Vascular Permeability through Juxtacrine Regulation of Endothelial Adherens Junctions


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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.


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. Presently, we have established a zebrafish model that exhibits significant excessive angiogenesis induced by high glucose, resembling the hyperangiogenic characteristics observed in proliferative diabetic retinopathy (PDR). Utilizing this model, we observed that glucose and noncaloric monosaccharides could induce excessive formation of blood vessels, especially intersegmental vessels (ISVs). The excessively branched vessels were observed to be formed by ectopic activation of quiescent endothelial cells (ECs) into tip cells. Single-cell transcriptomic sequencing analysis of the endothelial cells in the embryos exposed to high glucose revealed an augmented ratio of capillary ECs, proliferating ECs, and a series of upregulated proangiogenic genes. Further analysis and experiments validated that foxo1a mediated the excessive angiogenesis induced by monosaccharides by down-regulating the expression of marcksl1a . This study has provided new evidence showing the negative effects of noncaloric monosaccharides on the vascular system and the underlying mechanisms.

### Competing Interest Statement

The authors have declared no competing interest.

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

noncaloric-monosaccharides-induce-excessive-sprouting-angiogenesis-in-zebrafish-via-the-foxo1a-marcksl1a-signaling-pathway


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