Distal skin ischemic necrosis is a common complication in skin flap surgery. The pathogenesis of skin flap ischemic necrosis is unclear, and there is no clinical treatment available. Here, we used the 4 x 10 cm rat dorsal skin flap model to test our hypothesis that subcutaneous injection of vascular endothelial growth factor 165 (VEGF165) in skin flaps at the time of surgery is effective in augmentation of skin flap viability, which is associated with an increase in nitric oxide (NO) production, and the mechanism involves 1) an increase in skin flap blood flow in the early stage after surgery and 2) enhanced angiogenesis subsequently to sustain increased skin flap blood flow and viability. We observed that subcutaneous injection of VEGF165 in skin flaps at the time of surgery increased skin flap viability in a dose-dependent manner. Subcutaneous injection of VEGF165 at the dose of 2 microg/flap increased skin flap viability by 28% (P < 0.05; n = 8). Over 80% of this effect was blocked by intramuscular injection of the NO synthase (NOS) inhibitor Nomega-nitro-L-arginine (13 mg/kg) 45 min before surgery (P < 0.05; n = 8). The VEGF165 treatment also increased skin flap blood flow (2.68 +/- 0.63 ml x min(-1) x 100 g(-1)) compared with the control (1.26 +/- 0.10 ml x min(-1) x 100 g(-1); P < 0.05, n = 6) assessed 6 h postoperatively. There was no change in skin flap capillary density at this time point. VEGF165-induced increase in capillary density (32.2 +/- 1.1 capillaries/mm2; P < 0.05, n = 7) compared with control (24.6 +/- 1.4 capillaries/mm2) was seen 7 days postoperatively. There was also evidence to indicate that VEGF165-induced NO production in skin flaps was stimulated by activation of NOS activity followed by upregulation of NOS protein expression. These observations support our hypothesis and for the first time provide an important insight into the mechanism of acute local VEGF165 protein therapy in mitigation of skin flap ischemic necrosis.
Skin ischemic necrosis due to vasospasm and/or insufficient vascularity is the most common complication in the distal portion of the skin flap in reconstructive surgery. This project was designed to test our hypothesis that preoperative subdermal injection of adenoviral vectors encoding genes for vascular endothelial growth factor-165 (Ad.VEGF-165) or endothelial nitric oxide (NO) synthase (Ad.eNOS) effectively augments skin viability in skin flap surgery and that the mechanism of Ad.VEGF-165 gene therapy involves an increase in synthesis/release of the angiogenic and vasodilator factor NO. PBS (0.5 ml) or PBS containing Ad.VEGF-165, Ad.eNOS, or adenovirus (Ad.Null) was injected subdermally into the distal half of a mapped rat dorsal skin flap (4 × 10 cm) 7 days preoperatively, and skin flap viability was assessed 7 days postoperatively. Local subdermal gene therapy with 2 × 107–2 × 1010 plaque-forming units of VEGF-165 increased skin flap viability compared with PBS- or Ad.Null-injected control ( P < 0.05). Subdermal Ad.VEGF-165 and Ad.eNOS gene therapies were equally effective in increasing skin flap viability at 5 × 108 plaque-forming units. Subdermal Ad.VEGF-165 therapy was associated with upregulation of eNOS protein expression, Ca2+-dependent NOS activity, synthesis/release of NO, and increase in capillary density and blood flow in the distal portion of the skin flap. Injection of the NOS inhibitor Nω-nitro-l-arginine (15 mg/kg im), but not the cyclooxygenase inhibitor indomethacin (5 mg/kg im), 45 min preoperatively completely abolished the increase in skin flap blood flow and viability induced by Ad.VEGF-165 injected subdermally into the mapped skin flap 7 days preoperatively. We have demonstrated for the first time that 1) Ad.VEGF-165 and Ad.eNOS mapped skin flap injected subdermally into the mapped skin flap 7 days preoperatively are equally effective in augmenting viability in the rat dorsal skin flap compared with control, 2) the mechanism of subdermal Ad.VEGF-165 gene therapy in augmenting skin flap viability involves an increase in NO synthesis/release downstream of upregulation of eNOS protein expression and Ca2+-dependent NOS activity, and 3) the vasodilating effect of NO may predominantly mediate subdermal Ad.VEGF gene therapy in augmenting skin flap blood flow and viability.
Gross primary productivity (GPP) is the largest flux in the global carbon cycle and satellite‐based GPP estimates have long been used to study the trends and interannual variability of GPP. With recent updates to geostationary satellites, we can now explore the diurnal variability of GPP at a comparable spatial resolution to polar‐orbiting satellites and at temporal frequencies comparable to eddy covariance (EC) tower sites. We used observations from the Advanced Baseline Imager on the Geostationary Operational Environmental Satellite‐R series (GOES‐R) to test the ability of subdaily satellite data to capture the shifts in the diurnal course of GPP at an oak savanna EC site in California, USA that is subject to seasonal soil moisture declines. We compared three methods to estimate GPP: (a) a light‐use efficiency model, (b) a linear relationship between the product of near‐infrared reflectance of vegetation and photosynthetically active radiation (LIN‐NIRvP) and EC tower GPP, and (c) a light response curve (LRC‐NIRvP) between NIRvP and EC GPP. The LRC‐NIRvP achieved the lowest mean absolute error for winter (2 µmol CO2 m−2 s−1), spring (2.51 µmol CO2 m−2 s−1), summer (1.43 µmol CO2 m−2 s−1), and fall (1.35 µmol CO2 m−2 s−1). The ecosystem experienced the largest shift in daily peak GPP in relation to the peak of incoming solar radiation toward the morning hours during the dry summers. The LRC‐NIRvP and the light‐use efficiency model were in agreement with these patterns of a shift in peak daily GPP toward the morning hours during summer. Our results can help develop diurnal estimates of GPP from geostationary satellites that are sensitive to fluctuating environmental conditions during the day.
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