Vascular Permeability and Pathological Angiogenesis in Caveolin-1-Null Mice

Abstract

Caveolin-1, the signature protein of endothelial cell caveolae, has many important functions in vascular cells. Caveolae are thought to be the transcellular pathway by which plasma proteins cross normal capillary endothelium, but, unexpectedly, cav-1 ؊/؊ mice, which lack caveolae, have increased permeability to plasma albumin. The acute increase in vascular permeability induced by agents such as vascular endothelial growth factor (VEGF)-A occurs through venules, not capillaries, and particularly through the vesiculo-vacuolar organelle (VVO), a unique structure composed of numerous interconnecting vesicles and vacuoles that together span the venular endothelium from lumen to ablumen. Furthermore, the hyperpermeable blood vessels found in pathological angiogenesis, mother vessels, are derived from venules. The present experiments made use of cav-1 ؊/؊ mice to investigate the relationship between caveolae and VVOs and the roles of caveolin-1 in VVO structure in the acute vascular hyperpermeability induced by VEGF-A and in pathological angiogenesis and associated chronic vascular hyperpermeability. We found that VVOs expressed caveolin-1 variably but, in contrast to caveolae, were present in normal numbers and with apparently unaltered structure in cav-1 ؊/؊ mice. Nonetheless, VEGF-A-induced hyperpermeability was strikingly reduced in cav-1 ؊/؊ mice, as was pathological angiogenesis and associated chronic vascular hyperpermeability, whether induced by VEGF-A 164 or by a tumor. Thus, caveolin-1 is not necessary for VVO structure but may have important roles in regulating VVO function in acute vascular hyperpermeability and angiogenesis. (Am J Pathol

Altered Angiogenesis in Caveolin-1 Gene–Deficient Mice Is Restored by Ablation of Endothelial Nitric Oxide Synthase

“…By in vitro, ex vivo, and in vivo experiments, our results further confirm previous studies showing that the individual loss of eNOS 36 or caveolin-1 20,22 impairs the angiogenic response elicited by B16 melanoma cells inoculated in vivo. In addition, we show for the first time that reduced tumor angiogenesis in caveolin-1-null mice is due to unabated endothelial nitric oxide production, as genetic disruption of eNOS in the caveolin-1-null background partially or totally restores angiogenesis quantitatively.…”

“…21 Defective mobilization of endothelial progenitors in response to ischemia was further documented in caveolin-1-deficient mice. 38 However, using tumor angiogenesis assays, both an increase 18,19 and a decrease 20,22 in the number of angiogenic blood vessels have been reported. Studies reporting increased tumor angiogenesis also documented increased tumor growth in caveolin-1-null mice, 18,19 whereas studies reporting decreased angiogenesis showed decreased tumor growth.…”

“…Studies reporting increased tumor angiogenesis also documented increased tumor growth in caveolin-1-null mice, 18,19 whereas studies reporting decreased angiogenesis showed decreased tumor growth. 20,22 The method for numbering the tumor blood vessels has been suggested to explain the difference between these studies. 18 In our experiments, CD31 and ␣-smooth muscle cell actin staining of tumor sections confirmed the decreased number in vessels seen with the H&E staining in the caveolin-1 gene-deficient mice (not shown).…”

“…Decreased pathological neovascularization in caveolin-1-null mice has not been unanimously reported. Decreased angiogenesis was shown using bFGF-containing matrigel plugs, 20 VEGF-expressing adenoviral vector, 22 experimental colitis 23 or cerebral ischemia. 37 Reduced ischemic hindlimb reperfusion after femoral artery resection is also apparent in these mice.…”

Ezetimibe suppresses cholesterol accumulation in lipid-loaded vascular smooth muscle cells in vitro via MAPK signaling

“…The established Cav-1 knockout mouse line has confirmed the importance of Cav-1 for the formation of morphologically distinct caveolae [9,10] . In addition, Cav-1 is also involved in the maintenance of cellular cholesterol homeostasis and lipid transport.…”