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2018 ; 19
(5
): ä Nephropedia Template TP
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EphrinB2/EphB4 signaling regulates non-sprouting angiogenesis by VEGF
#MMPMID29643120
Groppa E
; Brkic S
; Uccelli A
; Wirth G
; Korpisalo-Pirinen P
; Filippova M
; Dasen B
; Sacchi V
; Muraro MG
; Trani M
; Reginato S
; Gianni-Barrera R
; Ylä-Herttuala S
; Banfi A
EMBO Rep
2018[May]; 19
(5
): ä PMID29643120
show ga
Vascular endothelial growth factor (VEGF) is the master regulator of
angiogenesis, whose best-understood mechanism is sprouting. However, therapeutic
VEGF delivery to ischemic muscle induces angiogenesis by the alternative process
of intussusception, or vascular splitting, whose molecular regulation is
essentially unknown. Here, we identify ephrinB2/EphB4 signaling as a key
regulator of intussusceptive angiogenesis and its outcome under therapeutically
relevant conditions. EphB4 signaling fine-tunes the degree of endothelial
proliferation induced by specific VEGF doses during the initial stage of
circumferential enlargement of vessels, thereby limiting their size and
subsequently enabling successful splitting into normal capillary networks.
Mechanistically, EphB4 neither inhibits VEGF-R2 activation by VEGF nor its
internalization, but it modulates VEGF-R2 downstream signaling through
phospho-ERK1/2. In vivo inhibitor experiments show that ERK1/2 activity is
required for EphB4 regulation of VEGF-induced intussusceptive angiogenesis.
Lastly, after clinically relevant VEGF gene delivery with adenoviral vectors,
pharmacological stimulation of EphB4 normalizes dysfunctional vascular growth in
both normoxic and ischemic muscle. These results identify EphB4 as a druggable
target to modulate the outcome of VEGF gene delivery and support further
investigation of its therapeutic potential.
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