Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells

Abstract

Vascular endothelial growth factor (VEGF)-A is a well-known major chemoattractant driver of angiogenesis -the formation of new blood vessels from pre-existing ones. However, the repellent factors that fine-tune this angiogenic process remain poorly characterized. We investigated the expression and functional role of endothelial cellderived semaphorin 3A (Sema3A) in retinal angiogenesis, using genetic mouse models. We found Sema3a mRNA expression in the ganglion cell layer and the presence of Sema3A protein on larger blood vessels and at the growing front of blood vessels in neonatal retinas. The Sema3A receptors neuropilin-1 and plexin-A1 were expressed by retinal blood vessels. To study the endothelial cellspecific role of Sema3A, we generated endothelial cell-specific Sema3A knockout mouse strains by constitutive or inducible vascular endothelial cadherin-Cre-mediated gene disruption. We found that in neonatal retinas of these mice, both the number and the length of tip cell filopodia were significantly increased and the leading edge growth pattern was irregular. Retinal explant experiments showed that recombinant Sema3A significantly decreased VEGF-A-induced filopodia formation. Endothelial cell-specific knockout of Sema3A had no impact on blood vessel density or skin vascular leakage in adult mice. These findings indicate that endothelial cell-derived Sema3A exerts repelling functions on VEGF-A-induced tip cell filopodia and that a lack of this signaling cannot be rescued by paracrine sources of Sema3A.

Bone marrow pericyte dysfunction in individuals with type 2 diabetes

“…6k–m ). Neuropilins play a central role in blood vessel physiology as receptors for semaphorin (SEMA) and VEGF isoforms [ 38 , 39 ]. Here, we found diabetes reduced NRP1 transcripts in bone marrow pericytes and increased SEMA6A ( p < 0.05 vs non-diabetic control individuals for both comparisons, Fig.…”

Class 3 semaphorins in cardiovascular development

“…The reported lack of vascular abnormalities in one study on Sema3a null mice 49 could be due to the use of an age-and-stage matching strategy to compare wild type and Sema3a null embryos; indeed, age-and-stage matching inherently overlooks the growth retardation phenotype that, as previously described, 50 usually characterize knockout embryos that display vascular remodeling defects, such as Sema3a null mice 43 . Of note, endothelial tip cells of murine retinal vascular spouts were found to express much more Sema3a mRNA than stalk ECs, 51 and EC-specific Sema3a knockout mice were recently described to exhibit a significantly increased number and length of endothelial tip cell filopodia in retinal vascular sprouts 52 . The latter finding emphasize how paracrine Sema3A secreted by non-vascular cells of adjacent tissues does not rescue the specific function(s) that autocrine EC-derived Sema3A exerts during sprouting angiogenesis.…”

Mesenchymal Stromal Cells Promote Retinal Vascular Repair by Modulating Sema3E and IL-17A in a Model of Ischemic Retinopathy

“…We previously highlighted the importance of neuron-derived signaling molecules on retinal endothelial cell function (Joyal et al, 2011;Rivera et al, 2013), particularly as it applies to guidance molecules of the class III semaphorins family (Sema3A-Sema3G), which are derived from retinal ganglion cells (RGCs), and are key regulators of developmental and pathological angiogenesis in the retina (Fukushima et al, 2011;Joyal et al, 2011;Kim et al, 2011;Buehler et al, 2013;Yang et al, 2015;Ochsenbein et al, 2016). Semaphorins can in turn affect the activity of myeloid cells (Ito et al, 2012;Neufeld et al, 2016).…”