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• W1968864231 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-A164 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. 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-A164 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. Caveolae (also referred to as plasmalemmal vesicles) were described by Palade and Bruns in capillary endothelial cells as 50- to 100-nm diameter smooth membrane-bound vesicles.1Palade GE Bruns RR Structural modulations of plasmalemmal vesicles.J Cell Biol. 1968; 37: 633-649Crossref PubMed Scopus (301) Google Scholar, 2Bruns RR Palade GE Studies on blood capillaries. II. Transport of ferritin molecules across the wall of muscle capillaries.J Cell Biol. 1968; 37: 277-299Crossref PubMed Scopus (326) Google Scholar Palade and Bruns proposed that caveolae shuttled across capillary endothelium from lumen to ablumen, carrying with them “cargoes” of plasma and in this manner provided the small amounts of plasma proteins that are required for maintaining tissue health. Later work demonstrated that caveolae could also form short chains of two to three linked vesicles that spanned the short distance across the capillary endothelium.3Simionescu N Cellular aspects of transcapillary exchange.Physiol Rev. 1983; 63: 1536-1579Crossref PubMed Scopus (216) Google Scholar Together these studies implied that, whether shuttling or interconnected into short chains, capillary caveolae were de facto the elusive “large pores” that physiologists had postulated to account for plasma protein extravasation.4Rippe B Haraldsson B Transport of macromolecules across microvascular walls: the two-pore theory.Physiol Rev. 1994; 74: 163-219Crossref PubMed Scopus (9) Google Scholar, 5Dvorak A Electron microscopic-facilitated understanding of endothelial cell biology.in: Aird W Contributions Established during the 1950s and 1960s. Cambridge University Press, New York2007: 643Google Scholar Since their initial discovery, much has been learned about caveolae and their signature protein, caveolin.6Carver LA Schnitzer JE Caveolae: mining little caves for new cancer targets.Nat Rev Cancer. 2003; 3: 571-581Crossref PubMed Scopus (229) Google Scholar, 7Frank PG Pavlides S Cheung MW Daumer K Lisanti MP Role of caveolin-1 in the regulation of lipoprotein metabolism.Am J Physiol Cell Physiol. 2008; 295: C242-C248Crossref PubMed Scopus (107) Google Scholar, 8Frank PG Woodman SE Park DS Lisanti MP Caveolin, caveolae, and endothelial cell function.Arterioscler Thromb Vasc Biol. 2003; 23: 1161-1168Crossref PubMed Scopus (302) Google Scholar, 9Gratton JP Bernatchez P Sessa WC Caveolae and caveolins in the cardiovascular system.Circ Res. 2004; 94: 1408-1417Crossref PubMed Scopus (270) Google Scholar, 10Navarro A Anand-Apte B Parat MO A role for caveolae in cell migration.FASEB J. 2004; 18: 1801-1811Crossref PubMed Scopus (142) Google Scholar Caveolin is thought to be necessary for caveolae formation and overexpression of caveolin can induce caveolae in cells that normally lack them.11Vallejo J Hardin CD Expression of caveolin-1 in lymphocytes induces caveolae formation and recruitment of phosphofructokinase to the plasma membrane.FASEB J. 2005; 19: 586-587PubMed Google Scholar Caveolin exists in three isoforms.12Park DS Woodman SE Schubert W Cohen AW Frank PG Chandra M Shirani J Razani B Tang B Jelicks LA Factor SM Weiss LM Tanowitz HB Lisanti MP Caveolin-1/3 double-knockout mice are viable, but lack both muscle and non-muscle caveolae, and develop a severe cardiomyopathic phenotype.Am J Pathol. 2002; 160: 2207-2217Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 13Cohen AW Hnasko R Schubert W Lisanti MP Role of caveolae and caveolins in health and disease.Physiol Rev. 2004; 84: 1341-1379Crossref PubMed Scopus (737) Google Scholar, 14Williams TM Lisanti MP The Caveolin genes: from cell biology to medicine.Ann Med. 2004; 36: 584-595Crossref PubMed Scopus (313) Google Scholar The first two isoforms, cav-1 and cav-2, are highly expressed in vascular endothelium, pericytes and smooth muscle, among other cell types, whereas cav-3 is confined to muscle.15Tang Z Scherer PE Okamoto T Song K Chu C Kohtz DS Nishimoto I Lodish HF Lisanti MP Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle.J Biol Chem. 1996; 271: 2255-2261Crossref PubMed Scopus (610) Google Scholar Caveolae and caveolin have many functions besides plasma protein transport, including regulation of cholesterol homeostasis and sorting of signaling molecules such as endothelial nitric oxide synthase, heterotrimeric G proteins, and nonreceptor tyrosine kinases.7Frank PG Pavlides S Cheung MW Daumer K Lisanti MP Role of caveolin-1 in the regulation of lipoprotein metabolism.Am J Physiol Cell Physiol. 2008; 295: C242-C248Crossref PubMed Scopus (107) Google Scholar, 9Gratton JP Bernatchez P Sessa WC Caveolae and caveolins in the cardiovascular system.Circ Res. 2004; 94: 1408-1417Crossref PubMed Scopus (270) Google Scholar, 14Williams TM Lisanti MP The Caveolin genes: from cell biology to medicine.Ann Med. 2004; 36: 584-595Crossref PubMed Scopus (313) Google Scholar, 16Frank PG Lisanti MP Caveolin-1 and caveolae in atherosclerosis: differential roles in fatty streak formation and neointimal hyperplasia.Curr Opin Lipidol. 2004; 15: 523-529Crossref PubMed Scopus (69) Google Scholar, 17Frank PG Pavlides S Lisanti MP Caveolae and transcytosis in endothelial cells: role in atherosclerosis.Cell Tissue Res. 2009; 335: 41-47Crossref PubMed Scopus (111) Google Scholar Cav-1−/− mice have contributed much to our understanding of caveolin and caveolae. Cav-1−/− mice are viable and fertile but lack caveolae and exhibit various types of vascular dysfunction, including impaired nitric oxide and Ca2+ signaling.12Park DS Woodman SE Schubert W Cohen AW Frank PG Chandra M Shirani J Razani B Tang B Jelicks LA Factor SM Weiss LM Tanowitz HB Lisanti MP Caveolin-1/3 double-knockout mice are viable, but lack both muscle and non-muscle caveolae, and develop a severe cardiomyopathic phenotype.Am J Pathol. 2002; 160: 2207-2217Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 18Drab M Verkade P Elger M Kasper M Lohn M Lauterbach B Menne J Lindschau C Mende F Luft FC Schedl A Haller H Kurzchalia TV Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice.Science. 2001; 293: 2449-2452Crossref PubMed Scopus (1313) Google Scholar, 19Medina FA de Almeida CJ Dew E Li J Bonuccelli G Williams TM Cohen AW Pestell RG Frank PG Tanowitz HB Lisanti MP Caveolin-1-deficient mice show defects in innate immunity and inflammatory immune response during Salmonella enterica serovar Typhimurium infection.Infect Immun. 2006; 74: 6665-6674Crossref PubMed Scopus (75) Google Scholar, 20Razani B Engelman JA Wang XB Schubert W Zhang XL Marks CB Macaluso F Russell RG Li M Pestell RG Di Vizio D Hou Jr, H Kneitz B Lagaud G Christ GJ Edelmann W Lisanti MP Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities.J Biol Chem. 2001; 276: 38121-38138Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 21Schubert W Sotgia F Cohen AW Capozza F Bonuccelli G Bruno C Minetti C Bonilla E Dimauro S Lisanti MP Caveolin-1−/−- and caveolin-2−/−-deficient mice both display numerous skeletal muscle abnormalities, with tubular aggregate formation.Am J Pathol. 2007; 170: 316-333Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 22Woodman SE Ashton AW Schubert W Lee H Williams TM Medina FA Wyckoff JB Combs TP Lisanti MP Caveolin-1 knockout mice show an impaired angiogenic response to exogenous stimuli.Am J Pathol. 2003; 162: 2059-2068Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar However, there is controversy on some other points, such as whether tumor growth and angiogenesis are altered in cav-1−/− mice, and, if so, in what direction and by what mechanism.22Woodman SE Ashton AW Schubert W Lee H Williams TM Medina FA Wyckoff JB Combs TP Lisanti MP Caveolin-1 knockout mice show an impaired angiogenic response to exogenous stimuli.Am J Pathol. 2003; 162: 2059-2068Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 23Bauer PM Yu J Chen Y Hickey R Bernatchez PN Looft-Wilson R Huang Y Giordano F Stan RV Sessa WC Endothelial-specific expression of caveolin-1 impairs microvascular permeability and angiogenesis.Proc Natl Acad Sci USA. 2005; 102: 204-209Crossref PubMed Scopus (131) Google Scholar, 24Brouet A DeWever J Martinive P Havaux X Bouzin C Sonveaux P Feron O Antitumor effects of in vivo caveolin gene delivery are associated with the inhibition of the proangiogenic and vasodilatory effects of nitric oxide.FASEB J. 2005; 19: 602-604PubMed Google Scholar, 25DeWever J Frerart F Bouzin C Baudelet C Ansiaux R Sonveaux P Gallez B Dessy C Feron O Caveolin-1 is critical for the maturation of tumor blood vessels through the regulation of both endothelial tube formation and mural cell recruitment.Am J Pathol. 2007; 171: 1619-1628Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 26Griffoni C Spisni E Santi S Riccio M Guarnieri T Tomasi V Knockdown of caveolin-1 by antisense oligonucleotides impairs angiogenesis in vitro and in vivo.Biochem Biophys Res Commun. 2000; 276: 756-761Crossref PubMed Scopus (81) Google Scholar, 27Lin MI Yu J Murata T Sessa WC Caveolin-1-deficient mice have increased tumor microvascular permeability, angiogenesis, and growth.Cancer Res. 2007; 67: 2849-2856Crossref PubMed Scopus (114) Google Scholar, 28Liu J Razani B Tang S Terman BI Ware JA Lisanti MP Angiogenesis activators and inhibitors differentially regulate caveolin-1 expression and caveolae formation in vascular endothelial cells. Angiogenesis inhibitors block vascular endothelial growth factor-induced down-regulation of caveolin-1.J Biol Chem. 1999; 274: 15781-15785Crossref PubMed Scopus (165) Google Scholar, 29Sonveaux P Martinive P DeWever J Batova Z Daneau G Pelat M Ghisdal P Gregoire V Dessy C Balligand JL Feron O Caveolin-1 expression is critical for vascular endothelial growth factor-induced ischemic hindlimb collateralization and nitric oxide-mediated angiogenesis.Circ Res. 2004; 95: 154-161Crossref PubMed Scopus (168) Google Scholar Recently, cav-1−/− mice have been found to be systemically hyperpermeable to plasma albumin25DeWever J Frerart F Bouzin C Baudelet C Ansiaux R Sonveaux P Gallez B Dessy C Feron O Caveolin-1 is critical for the maturation of tumor blood vessels through the regulation of both endothelial tube formation and mural cell recruitment.Am J Pathol. 2007; 171: 1619-1628Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 30Rosengren BI Rippe A Rippe C Venturoli D Sward K Rippe B Transvascular protein transport in mice lacking endothelial caveolae.Am J Physiol Heart Circ Physiol. 2006; 291: H1371-H1377Crossref PubMed Scopus (53) Google Scholar, 31Schubert W Frank PG Woodman SE Hyogo H Cohen DE Chow CW Lisanti MP Microvascular hyperpermeability in caveolin-1 (−/−) knock-out mice. Treatment with a specific nitric-oxide synthase inhibitor, l-NAME, restores normal microvascular permeability in Cav-1 null mice.J Biol Chem. 2002; 277: 40091-40098Crossref PubMed Scopus (276) Google Scholar; this finding was unexpected in that caveolae have been thought to be necessary for transporting plasma proteins across capillary endothelium under basal conditions.1Palade GE Bruns RR Structural modulations of plasmalemmal vesicles.J Cell Biol. 1968; 37: 633-649Crossref PubMed Scopus (301) Google Scholar, 2Bruns RR Palade GE Studies on blood capillaries. II. Transport of ferritin molecules across the wall of muscle capillaries.J Cell Biol. 1968; 37: 277-299Crossref PubMed Scopus (326) Google Scholar, 3Simionescu N Cellular aspects of transcapillary exchange.Physiol Rev. 1983; 63: 1536-1579Crossref PubMed Scopus (216) Google Scholar However, vascular permeability is not of a single type.32Nagy JA Benjamin L Zeng H Dvorak AM Dvorak HF Vascular permeability, vascular hyperpermeability and angiogenesis.Angiogenesis. 2008; 11: 109-119Crossref PubMed Scopus (459) Google Scholar In contrast to the normal, low level basal vascular permeability (BVP) of normal tissues, two distinctly different types of increased vascular permeability are found in pathological conditions.32Nagy JA Benjamin L Zeng H Dvorak AM Dvorak HF Vascular permeability, vascular hyperpermeability and angiogenesis.Angiogenesis. 2008; 11: 109-119Crossref PubMed Scopus (459) Google Scholar Vascular permeabilizing factors, such as vascular endothelial growth factor (VEGF)-A, histamine, and others, induce acute vascular hyperpermeability (AVH), a characteristic feature of acute inflammation. Chronic vascular hyperpermeability (CVH), on the other hand, is found in the pathological angiogenesis induced by tumors, healing wounds, and chronic inflammatory diseases; as its name implies, CVH persists for long periods of time—days to weeks and sometimes indefinitely. AVH and CVH differ from BVP not only in terms of the much greater amounts of plasma that extravasate but also with respect to the microvessels that leak. BVP takes place in capillaries.2Bruns RR Palade GE Studies on blood capillaries. II. Transport of ferritin molecules across the wall of muscle capillaries.J Cell Biol. 1968; 37: 277-299Crossref PubMed Scopus (326) Google Scholar, 3Simionescu N Cellular aspects of transcapillary exchange.Physiol Rev. 1983; 63: 1536-1579Crossref PubMed Scopus (216) Google Scholar, 4Rippe B Haraldsson B Transport of macromolecules across microvascular walls: the two-pore theory.Physiol Rev. 1994; 74: 163-219Crossref PubMed Scopus (9) Google Scholar In contrast, AVH takes place primarily in postcapillary venules33Majno G Palade GE Studies on inflammation. 1. The effect of histamine and serotonin on vascular permeability: an electron microscopic study.J Biophys Biochem Cytol. 1961; 11: 571-605Crossref PubMed Google Scholar, 34Feng D Nagy J Brekken R Pettersson A Manseau E Pyne K Mulligan R Thorpe P Dvorak H Dvorak A Ultrastructural localization of the vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) receptor-2 (FLK-1, KDR) in normal mouse kidney and in the hyperpermeable vessels induced by VPF/VEGF-expressing tumors and adenoviral vectors.J Histochem Cytochem. 2000; : 545-556Crossref PubMed Scopus (103) Google Scholar, 35Feng D Nagy JA Dvorak AM Dvorak HF Different pathways of macromolecule extravasation from hyperpermeable tumor vessels.Microvasc Res. 2000; 59: 24-37Crossref PubMed Scopus (91) Google Scholar, 36Feng D Nagy JA Hipp J Dvorak HF Dvorak AM Vesiculo-vacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin.J Exp Med. 1996; 183: 1981-1986Crossref PubMed Scopus (256) Google Scholar, 37Feng D Nagy JA Pyne K Hammel I Dvorak HF Dvorak AM Pathways of macromolecular extravasation across microvascular endothelium in response to VPF/VEGF and other vasoactive mediators.Microcirculation. 1999; 6: 23-44Crossref PubMed Google Scholar and is thought to involve an organelle, the vesiculo-vacuolar organelle (VVO), that is uniquely present in venular endothelial cells. VVOs are grapelike clusters of hundreds of uncoated, trilaminar unit membrane-bound, interconnecting vesicles and vacuoles that extend across the relatively tall cytoplasm of venular endothelium from lumen to ablumen. The relationship of VVOs to caveolae is uncertain.36Feng D Nagy JA Hipp J Dvorak HF Dvorak AM Vesiculo-vacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin.J Exp Med. 1996; 183: 1981-1986Crossref PubMed Scopus (256) Google Scholar, 37Feng D Nagy JA Pyne K Hammel I Dvorak HF Dvorak AM Pathways of macromolecular extravasation across microvascular endothelium in response to VPF/VEGF and other vasoactive mediators.Microcirculation. 1999; 6: 23-44Crossref PubMed Google Scholar, 38Dvorak AM Kohn S Morgan ES Fox P Nagy JA Dvorak HF The vesiculo-vacuolar organelle (VVO): a distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation.J Leukoc Biol. 1996; 59: 100-115PubMed Google Scholar, 39Dvorak AM Feng D The vesiculo-vacuolar organelle (VVO). A new endothelial cell permeability organelle.J Histochem Cytochem. 2001; 49: 419-432Crossref PubMed Scopus (213) Google Scholar, 40Kohn S Nagy JA Dvorak HF Dvorak AM Pathways of macromolecular tracer transport across venules and small veins. Structural basis for the hyperpermeability of tumor blood vessels.Lab Invest. 1992; 67: 596-607PubMed Google Scholar Unlike caveolae, which are of relatively uniform size, the vesicles and vacuoles that comprise VVOs vary widely in size from caveolae-sized vesicles to those with a cross-sectional areas more than 10-fold greater.37Feng D Nagy JA Pyne K Hammel I Dvorak HF Dvorak AM Pathways of macromolecular extravasation across microvascular endothelium in response to VPF/VEGF and other vasoactive mediators.Microcirculation. 1999; 6: 23-44Crossref PubMed Google Scholar They attach to each other and to the endothelial plasma membrane by stomata that are normally closed by thin diaphragms. In this respect, VVO stomata and diaphragms closely resemble the analogous structures by which caveolae attach to each other and to the luminal and abluminal plasma membranes of capillary endothelium.36Feng D Nagy JA Hipp J Dvorak HF Dvorak AM Vesiculo-vacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin.J Exp Med. 1996; 183: 1981-1986Crossref PubMed Scopus (256) Google Scholar, 37Feng D Nagy JA Pyne K Hammel I Dvorak HF Dvorak AM Pathways of macromolecular extravasation across microvascular endothelium in response to VPF/VEGF and other vasoactive mediators.Microcirculation. 1999; 6: 23-44Crossref PubMed Google Scholar, 38Dvorak AM Kohn S Morgan ES Fox P Nagy JA Dvorak HF The vesiculo-vacuolar organelle (VVO): a distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation.J Leukoc Biol. 1996; 59: 100-115PubMed Google Scholar, 41Stan RV Endothelial stomatal and fenestral diaphragms in normal vessels and angiogenesis.J Cell Mol Med. 2007; 11: 621-643Crossref PubMed Scopus (102) Google Scholar On exposure to acute permeabilizing agents such as VEGF or histamine, the diaphragms interconnecting VVO vesicles and vacuoles open to provide a trans-endothelial cell pathway for plasma extravasation.36Feng D Nagy JA Hipp J Dvorak HF Dvorak AM Vesiculo-vacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin.J Exp Med. 1996; 183: 1981-1986Crossref PubMed Scopus (256) Google Scholar, 37Feng D Nagy JA Pyne K Hammel I Dvorak HF Dvorak AM Pathways of macromolecular extravasation across microvascular endothelium in response to VPF/VEGF and other vasoactive mediators.Microcirculation. 1999; 6: 23-44Crossref PubMed Google Scholar, 42Feng D Nagy JA Hipp J Pyne K Dvorak HF Dvorak AM Reinterpretation of endothelial cell gaps induced by vasoactive mediators in guinea-pig, mouse and rat: many are transcellular pores.J Physiol. 1997; 504: 747-761Crossref PubMed Scopus (91) Google Scholar Others have reported leakage through a paracellular route, independent of VVOs.43Majno G Shea SM Leventhal M Endothelial contraction induced by histamine-type mediators: an electron microscopic study.J Cell Biol. 1969; 42: 647-672Crossref PubMed Scopus (625) Google Scholar, 44Baluk P Hirata A Thurston G Fujiwara T Neal CR Michel CC McDonald DM Endothelial gaps: time course of formation and closure in inflamed venules of rats.Am J Physiol. 1997; 272: L155-L170PubMed Google Scholar In CVH, yet another type of blood vessel, the “mother” vessel, accounts for the bulk of vascular hyperpermeability.45Nagy JA Feng D Vasile E Wong WH Shih SC Dvorak AM Dvorak HF Permeability properties of tumor surrogate blood vessels induced by VEGF-A.Lab Invest. 2006; 86: 767-780PubMed Scopus (95) Google Scholar Mother vessels are greatly enlarged, thin-walled, pericyte-poor sinusoids that derive from pre-existing normal venules after longer exposures to VEGF and other angiogenic stimuli.46Pettersson A Nagy JA Brown LF Sundberg C Morgan E Jungles S Carter R Krieger JE Manseau EJ Harvey VS Eckelhoefer IA Feng D Dvorak AM Mulligan RC Dvorak HF Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor.Lab Invest. 2000; 80: 99-115Crossref PubMed Scopus (363) Google Scholar VVOs participate in mother vessel formation and associated CVH.45Nagy JA Feng D Vasile E Wong WH Shih SC Dvorak AM Dvorak HF Permeability properties of tumor surrogate blood vessels induced by VEGF-A.Lab Invest. 2006; 86: 767-780PubMed Scopus (95) Google Scholar, 47Nagy JA Dvorak AM Dvorak HF VEGF-A and the induction of pathological angiogenesis.Annu Rev Pathol. 2007; 2: 251-275Crossref PubMed Scopus (313) Google Scholar The experiments reported here made use of cav-1−/− mice to investigate the relationship between caveolae and VVOs and the role of caveolin-1 in VVO structure, in AVH and CVH, and in pathological angiogenesis. We report here that some, but not all, VVO vesicles and vacuoles express caveolin-1. Nonetheless, VVOs are present in normal numbers and with unaltered structure in cav-1−/− mice. Further, we find that AVH and CVH are strikingly reduced in cav-1−/− mice. Angiogenesis is also reduced in cav-1−/− mice, whether induced by an adenoviral vector expressing VEGF-A164 (Ad-VEGF-A164) or by a tumor, the B16 melanoma. Four- to 6-week-old female wild-type C57BL/6 and caveolin 1 knockout (cav-1−/−) mice were obtained from The Jackson Laboratory (Bar Harbor, ME). Angiogenesis was induced in flank skin either with (Ad-VEGF-A164)46Pettersson A Nagy JA Brown LF Sundberg C Morgan E Jungles S Carter R Krieger JE Manseau EJ Harvey VS Eckelhoefer IA Feng D Dvorak AM Mulligan RC Dvorak HF Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor.Lab Invest. 2000; 80: 99-115Crossref PubMed Scopus (363) Google Scholar, 47Nagy JA Dvorak AM Dvorak HF VEGF-A and the induction of pathological angiogenesis.Annu Rev Pathol. 2007; 2: 251-275Crossref PubMed Scopus (313) Google Scholar, 48Nagy JA Shih SC Wong WH Dvorak AM Dvorak HF The adenoviral vector angiogenesis/lymphangiogenesis assay.Methods Enzymol. 2008; 444: 43-64Crossref PubMed Scopus (20) Google Scholar or with the B16 melanoma.49Zeng H Qin L Zhao D Tan X Manseau EJ Van Hoang M Senger DR Brown LF Nagy JA Dvorak HF Orphan nuclear receptor TR3/Nur77 regulates VEGF-A-induced angiogenesis through its transcriptional activity.J Exp Med. 2006; 203: 719-729Crossref PubMed Scopus (131) Google Scholar All studies were performed under protocols approved by the Beth Israel Deaconess Medical Center Institutional Animal Care and Use Committee. Animals were sacrificed by CO2 narcosis. Flank skin was fixed in 4% paraformaldehyde and processed either for frozen or paraffin sections and immunohistochemical analysis, as described previously.50Feng D Nagy JA Pyne K Dvorak HF Dvorak AM Ultrastructural localization of platelet endothelial cell adhesion molecule (PECAM-1. CD31) in vascular endothelium.J Histochem Cytochem. 2004; 52: 87-101Crossref PubMed Scopus (54) Google Scholar Two different rabbit polyclonal antibodies, one directed against N-terminal amino acids 1 to 97 (BD Biosciences, San Jose, CA) and the other against N-terminal amino acids 1 to 20 (Santa Cruz Biotechnology Inc., Santa Cruz, CA), were used to identify caveolin-1. Mean vascular density was calculated by counting CD31-positive structures with lumens in the five most highly vascularized fields at ×400 magnification. Statistical analysis was performed using an unpaired t-test. Tissues were fixed and processed for electron microscopy as described previously.51Dvorak A Procedural guide to specimen handling for the ultrastructural pathology service laboratory.J Electron Microsc Tech. 1987; 6: 255-301Crossref Scopus (58) Google Scholar Morphometric analysis was performed on randomly selected electron micrographs of wild-type and cav-1−/− flank skin venules and capillaries for quantification of VVOs, vesicles, and caveolae.35Feng D Nagy JA Dvorak AM Dvorak HF Different pathways of macromolecule extravasation from hyperpermeable tumor vessels.Microvasc Res. 2000; 59: 24-37Crossref PubMed Scopus (91) Google Scholar, 37Feng D Nagy JA Pyne K Hammel I Dvorak HF Dvorak AM Pathways of macromolecular extravasation across microvascular endothelium in response to VPF/VEGF and other vasoactive mediators.Microcirculation. 1999; 6: 23-44Crossref PubMed Google Scholar Data were analyzed with the Kruskal-Wallis nonparametric analysis of variance test and with Dunn’s multiple comparisons test. Immuno-nanogold cytochemistry was performed as described previously.50Feng D Nagy JA Pyne K Dvorak HF Dvorak AM Ultrastructural localization of platelet endothelial cell adhesion molecule (PECAM-1. CD31) in vascular endothelium.J Histochem Cytochem. 2004; 52: 87-101Crossref PubMed Scopus (54) Google Scholar Tissues were fixed for 4 hours at room temperature in 4% paraformaldehyde-0.02 mol/L PBS, pH 7.4, and were washed in 0.02 mol/L PBS, pH 7.4. before immersion in 30% sucrose in 0.02 mol/L PBS, pH 7.4, overnight at 4°C. Tissues were embedded in OCT compound (Miles, Elkhart, IN), snap-frozen, and stored in liquid nitrogen. The same two rabbit polyclonal antibodies used for light microscopic immunohistochemistry were used. Ten-micrometer frozen sections were cut, collected on precleaned glass slides, air-dried for 20 minutes, and processed as described previously,50Feng D Nagy JA Pyne K Dvorak HF Dvorak AM Ultrastructural localization of platelet endothelial cell adhesion molecule (PECAM-1. CD31) in vascular endothelium.J Histochem Cytochem. 2004; 52: 87-101Crossref PubMed Scopus (54) Google Scholar except for differences in the antibodies used. After immunocytochemistry, sections were stained either with uranyl acetate or lead citrate or left unstained and examined in a Philips CM10 transmission electron microscope. Four control experiments were performed to ensure the specificity of immuno-nanogold staining: (i) replace the primary antibody with an irrelevant rabbit IgG; (ii) omit the primary antibody; (iii) omit the secondary antibody; and (iv) omit the HQ silver enhancement step. The Miles assay was performed as described previously.45Nagy JA Feng D Vasile E Wong WH Shih SC Dvorak AM Dvora" @default.
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• W1968864231 date "2009-10-01" @default.
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• W1968864231 title "Vascular Permeability and Pathological Angiogenesis in Caveolin-1-Null Mice" @default.
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