Reevaluation of the role of VEGF-B suggests a restricted role in the revascularization of the ischemic myocardium

Abstract

Objective: The endogenous role of the VEGF family member vascular endothelial growth factor-B (VEGF-B) in pathological angiogenesis remains unclear.

Methods and results: We studied the role of VEGF-B in various models of pathological angiogenesis using mice lacking VEGF-B (VEGF-B(-/-)) or overexpressing VEGF-B(167). After occlusion of the left coronary artery, VEGF-B deficiency impaired vessel growth in the ischemic myocardium whereas, in wild-type mice, VEGF-B(167) overexpression enhanced revascularization of the infarct and ischemic border zone. By contrast, VEGF-B deficiency did not affect vessel growth in the wounded skin, hypoxic lung, ischemic retina, or ischemic limb. Moreover, VEGF-B(167) overexpression failed to enhance vascular growth in the skin or ischemic limb.

Conclusions: VEGF-B appears to have a relatively restricted angiogenic activity in the ischemic heart. These insights might offer novel therapeutic opportunities.

Figure 1

A and B, Morphometric analysis revealed a reduced number of TM⁺ and SMA⁺ vessels in the infarcted area of VEGF-B^−/− mice, as compared to WT animals (*P<0.05) or to VEGF-B^−/− mice, treated with rhVEGF-B₁₆₇ (#P<0.05 vs no treatment). C–F, Immunostaining showed increased TM⁺ and SMA⁺ vessels after delivery of rhVEGF-B₁₆₇ to WT mice. G and H, Systemic injection of Ad.hVEGF-B₁₆₇ stimulates the growth of TM⁺ and SMA⁺ vessels in the infarct area and border zone of WT mice (*P<0.05). Scale bars: 50 μm.

Figure 2

A–C, Skin wound healing is comparable in WT and VEGF-B^−/− mice as analyzed by measurement of the wound width (A), and illustrated by macroscopic inspection (B and C).

Figure 3

A and B, Immunolabeling for CD31 showed comparable vessel densities in regenerating gastrocnemius muscles of Ad.RR5 or Ad.hVEGF-B₁₆₇ injected mice. C and D, Double staining for β-Gal (green cells, marked by an asterisk) and CD31 revealed an identical vascularization pattern in gastrocnemius muscles, injected with control or VEGF-B₁₆₇ overexpressing myoblasts. E, Capillary-to-myocyte ratio is comparable in normal or ischemic limbs, injected with control or VEGF-B₁₆₇ over-expressing myoblasts. Scale bars: 50 μm.

Figure 4

A-H, Double immunostaining of β-Gal and CD31 (A, B, E, F) or SMA (C, D, G, H) in normal and ischemic heart (A–D) or skeletal muscle (E–H) sections of LacZ-tagged Flt-1 mice revealed labeling of Flt-1 expressing cells in most CD31⁺ cells (arrowheads) and in all SMA⁺ cells (arrows). Scale bars: 50 μm.