Vascular Endothelial Growth Factor (VEGF) isoform expression and activity in human and murine lung injury.

BACKGROUND: The properties of vascular endothelial growth factor (VEGF) as a potent vascular permogen and mitogen have led to investigation of its potential role in lung injury. Alternate spliced VEGF transcript generates several isoforms with potentially differing functions. The purpose of this study was to determine VEGF isoform expression and source in normal and ARDS subjects and investigate the expression and regulation of VEGF isoforms by human alveolar type 2 (ATII) cells. METHODS: VEGF protein expression was assessed immunohistochemically in archival normal and ARDS human lung tissue. VEGF isoform mRNA expression was assessed in human and murine lung tissue. Purified ATII cells were cultured with proinflammatory cytokines prior to RNA extraction/cell supernatant sampling/proliferation assay. MEASUREMENTS AND MAIN RESULTS: VEGF was expressed on alveolar epithelium, vascular endothelium and alveolar macrophages in normal and ARDS human lung tissue. Increases in VEGF expression were detected in later ARDS in comparison to both normal subjects and early ARDS (p < 0.001). VEGF121, VEGF165 and VEGF189 isoform mRNA expression increased in later ARDS (p < 0.05). The ratio of soluble to cell-associated isoforms was lower in early ARDS than normal subjects and later ARDS and also in murine lung injury. ATII cells constitutionally produced VEGF165 and VEGF121 protein which was increased by LPS (p < 0.05). VEGF165 upregulated ATII cell proliferation (p < 0.001) that was inhibited by soluble VEGF receptor 1 (sflt) (p < 0.05). CONCLUSION: These data demonstrate that changes in VEGF isoform expression occur in ARDS which may be related to their production by and mitogenic effect on ATII cells; with potentially significant clinical consequences.

Vascular endothelial growth factor receptor and coreceptor expression in human acute respiratory distress syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is characterized by the development of noncardiogenic pulmonary edema, which has been related to the bioactivity of vascular endothelial growth factor (VEGF). Vascular endothelial growth factor receptors and coreceptors regulate this bioactivity. We hypothesized VEGF receptors 1 and 2 (VEGFR1, VEGFR2) and coreceptor neuropilin-1 (NRP-1) would be expressed in human lung tissue with a significant change in expression in ARDS lung. METHODS: Archival "normal" (no lung pathology and non-ARDS), "early" (within 48 hours), and "later" (after day 7) ARDS lung-tissue sections (n = 5) were immunostained for VEGFR1, VEGFR2, and NRP-1 from human subjects (n = 4). Staining was assessed densitometrically using Histometrix software. RESULTS: VEGFR1, VEGFR2, and NRP-1 were expressed on both sides of the alveolar-capillary membrane in both normal and ARDS human lung tissue. In later ARDS, there was a significant up-regulation of VEGFR1 and VEGFR2 versus normal and early ARDS (P < .0001). Neuropilin-1 was down-regulated in early ARDS versus normal lung (P < .05), with normalization in later ARDS (P < .001). CONCLUSION: Differential temporal VEGFR1, VEGFR2, and NRP-1 up-regulation occurs in human ARDS, providing evidence of further functional regulation of VEGF bioactivity via VEGFR2 consistent with a protective role for VEGF in lung injury recovery. The mechanisms behind these observations remain to be clarified.