Islet vascularization is regulated by primary endothelial cilia via VEGF-A-dependent signaling

Abstract

Islet vascularization is essential for intact islet function and glucose homeostasis. We have previously shown that primary cilia directly regulate insulin secretion. However, it remains unclear whether they are also implicated in islet vascularization. At eight weeks, murine Bbs4-/-islets show significantly lower intra-islet capillary density with enlarged diameters. Transplanted Bbs4-/- islets exhibit delayed re-vascularization and reduced vascular fenestration after engraftment, partially impairing vascular permeability and glucose delivery to β-cells. We identified primary cilia on endothelial cells as the underlying cause of this regulation, via the vascular endothelial growth factor-A (VEGF-A)/VEGF receptor 2 (VEGFR2) pathway. In vitro silencing of ciliary genes in endothelial cells disrupts VEGF-A/VEGFR2 internalization and downstream signaling. Consequently, key features of angiogenesis including proliferation and migration are attenuated in human BBS4 silenced endothelial cells. We conclude that endothelial cell primary cilia regulate islet vascularization and vascular barrier function via the VEGF-A/VEGFR2 signaling pathway.

The Role of Vascular Cells in Pancreatic Beta-Cell Function

“…Endothelial cells also play a key role in islet development. The reciprocal influences of β-cells and islet endothelial cells affect development of both the vasculature ( 40 ) and β-cells ( 41 , 42 ). Evidence indicates that β-cells are unlikely to synthesize their own ECM components, and that developmental expression of angiogenic protein VEGFA from β-cells is vital to encourage the islet vascularisation required for basement membrane formation in developing islets ( 25 , 43 ).…”

Pericyte control of pancreatic islet blood flow impacts glucose homeostasis

“…1b). This model has been used extensively to study islet blood vessels because the revascularization of the graft faithfully reconstitutes the structural elements of the vasculature of the islet in the native pancreas [18][19][20][21][22][23][24][25][26] . Of note, intraocular islet grafts restore and maintain normoglycemia a couple of weeks after transplantation (Supplementary Fig.…”

Fibroblast growth factor 7 releasing particles enhance islet engraftment and improve metabolic control following islet transplantation in mice with diabetes

“…This study demonstrates that modulation of the liver niche by FGF7‐GAL‐PLGA particles is a potential therapeutic strategy for increasing islet engraftment and islet transplant outcomes in man. FGF7 may increase engraftment of islets by stimulating angiogenesis via VEGF induction directly 21 or indirectly 46,47 in keeping with increased hepatic CD31 staining at 72 h posttransplant in recipient mice. We did not detect VEGF‐A in liver; the immunofluorescence technique may not be sensitive enough to detect VEGF‐A at low levels or it may be upregulated at a different time point.…”

“…GFs may promote islet engraftment through: (1) liver cell proliferation and immediate islet “trapping”; (2) upregulation of VEGF, promoting vasculogenesis and early islet vascularization; 20,21 (3) anti‐inflammatory activity, thereby aiding islet survival; 22,23 and (4) inhibition of T cell–mediated immune effects 24 reducing islet rejection.…”

“…FGF7 is a small polypeptide member of the FGF family that binds to the FGF7 receptor and has proliferative and antiapoptotic effects on epithelial cells including hepatocytes. 18,19 GFs may promote islet engraftment through: (1) liver cell proliferation and immediate islet "trapping"; (2) upregulation of VEGF, promoting vasculogenesis and early islet vascularization; 20,21 (3) anti-inflammatory activity, thereby aiding islet survival; 22,23 and (4) inhibition of T cell-mediated immune effects 24 reducing islet rejection.…”