The roles of vascular endothelial growth factor receptor (VEGFR)-2 and -3 as principal regulators of blood and lymphatic vessel effects of vascular endothelial growth factors (VEGFs) are well established, but the biology of VEGFR-1 is still poorly understood. VEGFR-1 appears to mediate ligand-specific actions. It also exists as a soluble decoy receptor and acts as a negative regulator of angiogenesis. However, VEGFR-1 activation by placental growth factor (PlGF) and VEGF-B stimulates vascular growth and may result in the mobilization of EPCs in vivo. VEGFR-1 also mediates monocyte chemotaxis. Neuropilin-1 and -2 are co-receptors for some VEGFs and amplify intracellular signals. Affinity to heparan sulfates and neuropilin co-receptors modulate the biological activities of different VEGFs. VEGF-C and -D are proteolytically processed into mature forms that also effectively bind to VEGFR-2. DAG = diacylglycerol; eNOS = endothelial nitric oxide synthase; EPC = endothelial precursor cell; IP₃ = inositol trisphosphate; MAPK = mitogen-activated protein kinase; NO = nitric oxide; NRP = neuropilin; PGI₂ = prostacyclin; PKC = protein kinase C; PLC = phospholipase gamma.

Lack of sufficient vascular endothelial growth factor (VEGF)-A results in endothelial dysfunction via diminished nitric oxide and prostacyclin production. Physiological levels maintain vascular homeostasis and protection while higher levels induce physiological vascular growth with sprouting angiogenesis and moderate capillary enlargement. Very high VEGF-A levels promote aberrant vascular growth, i.e., the formation of blood lacunae and glomeruloid bodies as well as significant tissue edema.

(A and F) CD31 immunostainings of normal rabbit skeletal muscle transduced intramuscularly with AdLacZ or adenoviral vascular endothelial growth factor (AdVEGF)-A at 6 days earlier demonstrate abundant enlargement of preexisting capillaries after AdVEGF-A gene transfer. (Insets) CD31 (blue) + BrDU (brown) double stainings show that capillary enlargement with AdVEGF-A occurs through cell proliferation (black arrowheads). Scale bar = 50 µ m. (B and G) Longitudinal contrast-enhanced ultrasound imaging of rabbit thighs shows that perfusion is increased up to 27-fold 6 days after AdVEGF-A gene transfer in the target muscle (inside brackets). (C and H) 3-dimensional (3D) reconstructions of the ultrasound data show the increase in blood flow in the whole vascular tree, including large vessels. (D and I) Transversal mid-thigh T₂*-weighted magnetic resonance imaging (MRI) using a superparamagnetic contrast agent (Resovist), which causes intensive signal loss in the AdVEGF-A transduced semimembranosus muscle (outlined with dashed lines) as the result of high contrast concentration, i.e., blood volume. (E and J) Blood volume MRI maps visualize the difference in blood volume between AdVEGF-A and AdLacZ-treated muscles. Muscle edema is obvious after AdVEGF-A gene transfer both in ultrasound and MRI. P = proximal end of the semimembranosus muscle; asterisks = free fluid in between muscles after AdVEGF-A gene transfer; white arrowheads = profound femoral artery; arrows = superficial femoral artery. The figure, excluding the insets, has been modified from Rissanen et al. (55) with the permission of Lippincott Williams & Wilkins.