Dynamic alterations in decoy VEGF receptor-1 stability regulate angiogenesis

Abstract

Blood vessel expansion is driven by sprouting angiogenesis of endothelial cells, and is essential for development, wound healing and disease. Membrane-localized vascular endothelial growth factor receptor-1 (mVEGFR1) is an endothelial cell-intrinsic decoy receptor that negatively modulates blood vessel morphogenesis. Here we show that dynamic regulation of mVEGFR1 stability and turnover in blood vessels impacts angiogenesis. mVEGFR1 is highly stable and constitutively internalizes from the plasma membrane. Post-translational palmitoylation of mVEGFR1 is a binary stabilization switch, and ligand engagement leads to depalmitoylation and lysosomal degradation. Trafficking of palmitoylation enzymes via Rab27a regulates mVEGFR1 stability, as reduced levels of Rab27a impaired palmitoylation of mVEGFR1, decreased its stability, and elevated blood vessel sprouting and in vivo angiogenesis. These findings identify a regulatory axis affecting blood vessel morphogenesis that highlights exquisite post-translational regulation of mVEGFR1 in its role as a molecular rheostat.

A Role of Agrin in Maintaining the Stability of Vascular Endothelial Growth Factor Receptor-2 during Tumor Angiogenesis

“…As such, we deciphered that total VEGFR2 protein was majorly de-stabilized within 1 h of blocking protein translation by cycloheximide (CHX) ( Figure 5F, top panel). Even though soluble Agrin treatment partially stabilized VEGFR2 within 1-2 h post-CHX treatment ( Figure 5F, top panel), we further analyzed its stability within a 1-h time frame, owing to the low half-life of VEGFR2 (Boucher et al, 2017). Pre-treatment with soluble Agrin strongly stabilized VEGFR2 within 15-60 min post-CHX treatment ( Figure 5F, bottom panel).…”

Rab27a Regulates Human Perivascular Adipose Progenitor Cell Differentiation

“…Using this approach, we identified numerous secretion-associated proteins that appeared to be enriched in human PVAT compared to including human subcutaneous white adipose tissue, including synaptotagmin-1, myosin-9, Rab11 and Rab27 (data not shown). Importantly, Rab27a is a well-established regulator of protein secretion and degradation [20, 27, 37], and regulates the function of multiple systems [38], including pancreatic beta cell release of insulin [22], VEGFR1 degradation during angiogenesis [39], cancer stem cell self-renewal [40], initiation of clotting cascades [41] and lytic granule exocytosis from cytotoxic T-cells [42]. Rab27a expression and function has not been studied in adipose tissue, and given its prominent role in regulating secretion, we validated expression in human PVAT.…”

“…Widely expressed, Rab27a regulates immune, metabolic and blood vessel function [21–23], and is linked to several human cancers. Unlike most Rab proteins, which share complementary and/or overlapping functions, loss of Rab27a is linked to disease.…”

“…Mice harboring a null mutation in Rab27a ( ashen ) are viable, but phenocopy several attributes of Griscelli Syndrome [25]. Mechanistically, Rab27a regulates Golgi-to-plasma membrane vesicle trafficking, and exosome secretion [26], although non-secretory functions have been reported [21, 27]. …”

Role of proangiogenic factors in the formation of placental barrier structures in pregnant women with congenital heart defects and anaemia

“…Незважаючи на тривимірну подібність із VEGF A, PlGF має властивість зв'язувати виключно VEGFR 1 рецептор, з високою спорідненістю порівняно з VEGF A і VEGF B (рис. 1) [1,3,4].…”