Heterogeneity of the angiogenic response induced in different normal adulttissues by vascular permeability factor/vascular endothelial growth factor

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is an angiogenic cytokine with potential for the treatment of tissue ischem ia. To investigate the properties of the new blood vessels induced by VPF/V EGF, we injected an adenoviral vector engineered to express murine VPF/VEGF (154) into several normal tissues of adult nude mice or rats. A dose-depend ent angiogenic response was induced in all tissues studied but was more int ense and persisted longer (months) in skin and fat than in heart or skeleta l muscle (less than or equal to 3 weeks). The initial response (within 18 h ours) was identical in all tissues studied and was characterized by microva scular hyperpermeability, edema, deposition of an extravascular fibrin gel, and the formation of enlarged, thin-walled pericyte-poor vessels ("mother" vessels). Mother vessels developed from preexisting microvessels after per icyte detachment and basement membrane degradation. Mother vessels were tra nsient structures that evolved variably in different tissues into smaller d aughter vessels, disorganized vessel tangles (glomeruloid bodies), and medi um-sized muscular arteries and veins. Vascular structures closely resemblin g mother vessels and each mother vessel derivative have been observed in be nign and malignant tumors, in other examples of pathological and physiologi cal angiogenesis, and in vascular malformations. Together these data sugges t that VPF/VEGF has a role in the pathogenesis of these entities. They also indicate that the angiogenic response induced by VPF/VEGF is heterogeneous and tissue specific. Finally, the muscular vessels that developed from mot her vessels in skin and perimuscle fat have the structure of collaterals an d could be useful clinically in the relief of tissue ischemia.