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Animal Model |
From the Departments of Molecular Pharmacology,* Cardiology, Anatomy and Structural Biology, and Cell Biology,¶ and the Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York
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Abstract |
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Recent studies using Cav-1 knockout (KO) mice have begun to address the in vivo functional role of endothelial cell caveolae. For example, ablation of Cav-1 gene expression results in alterations in tight-junction morphology and resultant microvascular hyperpermeability.6 Furthermore, Cav-1 KO mouse aortas demonstrate enhanced vasorelaxation when subjected to acetylcholine treatment7,8 because of constitutive activation of eNOS within Cav-1 KO endothelial cells. These data clearly demonstrate that Cav-1 and caveolae organelles play important roles in normal endothelial cell functions.
Angiogenesis is the formation of new blood vessels from pre-existing vessels.9 The process of angiogenesis is characterized by the following progression of events: vasodilation, increased vascular permeability, extracellular matrix degradation, endothelial cell proliferation/migration/differentiation, and periendothelial maturation. Examination of the molecular underpinnings of these events has revealed that angiogenesis is tightly regulated by an array of stimulators and inhibitors, at multiple steps in the process.
Previous studies have shown that caveolae can fuse with each other to form larger vesicular structures as part of the angiogenic response.10 Consistent with these studies, we have recently shown that recombinant overexpression of Cav-1 in cultured endothelial cells, thus driving enhanced caveolae formation, accelerates endothelial capillary tubule formation by nearly threefold.11 Conversely, transfection of Cav-1 anti-sense oligonucleotides into endothelial cells results in the marked reduction of capillary tubule formation using a three-dimensional fibrin gel assay or the chorioallantoic membrane angiogenesis system.12 Finally, using an in vitro Matrigel assay, we have demonstrated that down-regulation of Cav-1 via an anti-sense adenoviral approach reduces the number of capillary-like tubules more than 10-fold.11 Consistent with these findings, we have observed that Cav-1 expression appears to be down-regulated during the proliferation phase of angiogenesis, and then markedly up-regulated during the differentiation phase,11 as observed using endothelial cells in culture. Similarly, numerous previous reports show a lack of Cav-1 expression in transformed cells versus a high level of Cav-1 expression in fully differentiated cells.13,14
In this report, we present the first in vivo evidence that Cav-1 and caveolae organelles play a positive regulatory role in the process of pathological angiogenesis, using Cav-1 KO mice as a model system.
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Experimental Procedures |
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TopAbstractExperimental ProceduresResultsDiscussionReferences |
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All mice were housed in a barrier facility at the Institute for Animal Studies, Albert Einstein College of Medicine. The generation of Cav-1 KO and Cav-2 KO mice, in the C57B/6 background, was as previously described.7,15-17 Twelve- to 16-week-old wild-type (WT), Cav-1 KO, or Cav-2 KO mice were used for all of the studies described below.
Matrigel Angiogenesis Assay
Mice were mildly anesthetized with isoflurane. Growth factor-reduced Matrigel (Becton Dickinson, Mountain View, CA) supplemented with basic fibroblast growth factor (bFGF) (500 ng/plug; Upstate Biotechnology, Inc., Lake Placid, NY) was injected subcutaneously into the mid-lower abdominal region of each mouse. Growth factor-reduced Matrigel without bFGF was used as a negative control. Plugs were excised after 1 or 2.5 weeks after injection. The abdominal skeletal muscle was removed intact with each plug for purposes of orientation. Matrigel plugs were then fixed in 10% neutrally buffered formalin. Vessel counts were determined from hematoxylin and eosin (H&E)-stained sections of paraffin-embedded plugs, at a magnification of x20.
Tumor Angiogenesis Assay
We chose to use B16-F10 cells as they are derived from C57BL/6 mice and, thus, are immunologically compatible with the C57BL/6 mice (WT and Cav-1 KO) used in this study. B16-F10 cells (CRL-6475; ATCC, Rockville, MD) were cultured in Dulbecco’s modified Eagle’s medium containing 10% fetal bovine serum. When B16-F10 cells reached 
75% confluence, they were lightly trypsinized, washed twice, then resuspended in ice-cold phosphate-buffered saline. Mice were mildly anesthetized with isoflurane, then injected subcutaneously in both flanks with 0.75 x 106 cells per flank. Twelve days after injection, the tumors were excised from each mouse, and tumor weight and volume were determined. Tumor volume was assessed after excision using caliper measurements of three dimensions (Scienceware; Bel-Art Products). Tumors were then fixed in 10% neutrally buffered formalin. Vessel counts were determined from H&E-stained paraffin-embedded sections, at a magnification of x40.
Multiphoton Confocal Microscopy
WT or Cav-1 KO mice were mildly anesthetized with isoflurane. Growth factor-reduced Matrigel supplemented with bFGF (500 ng/plug) was injected subcutaneously into the mid-lower abdominal region of each mouse. One week after Matrigel injection, each mouse was injected through the tail vein with 2 mg/ml of rhodamine-conjugated dextran (Sigma Chemical Co., St. Louis, MO). Plugs were then excised and immediately viewed using a Bio-Rad Radiance 2000 MP multiphoton confocal microscope (Albert Einstein College of Medicine, Analytical Imaging Facility).
Electron Microscopic Ultrastructural Analysis
Exogenous tumors were fixed with 2.5% glutaraldehyde in 0.1 mol/L of cacodylate buffer postfixed with OsO4, and stained with uranyl acetate and lead citrate. Samples were examined under a JEOL 1200EX transmission electron microscope (Albert Einstein College of Medicine, Analytical Imaging Facility).
Statistical Analysis
The Student’s t-test was applied to data from test groups. A P value of 
0.05 was considered significant.
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Results |
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TopAbstractExperimental ProceduresResultsDiscussionReferences |
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Basic fibroblast growth factor (bFGF) is a proven in vivo angiogenic factor.18,19 Thus, we tested the necessity of Cav-1/caveolae for proper bFGF-induced vessel infiltration into Matrigel plugs. Matrigel supplemented with 500 ng/plug of bFGF was injected into the subcutaneous compartment of the lower abdominal region of WT or Cav-1 KO mice. The formed Matrigel plugs were then removed after 1 week.
Many of the plugs removed from WT mice clearly showed gross signs of increased vascular and red blood cell content, whereas none of the Cav-1 KO plugs showed such macroscopic features (Figure 1A)
. Histological analysis of Cav-1 KO plugs revealed marked cellular proliferation at the interface between the abdominal skeletal muscle and the outer boundary of the plug; interestingly, this localized cellular proliferation was not observed in WT plugs (Figure 1B
, top). In addition, the number and depth of penetration of blood vessels was clearly reduced in Cav-1 KO mouse plugs, as compared with WT plugs (Figure 1B
, bottom).
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Multiphoton fluorescence microscopy allows for the observation of fluorescent indicators deep within tissues. Thus, we used multiphoton fluorescence microscopy to assess the depth of vessel infiltration into Matrigel plugs. WT or Cav-1 KO mice containing bFGF-supplemented Matrigel plugs for 1 week were infused intravascularly with rhodamine-labeled dextran. Plugs were then removed and examined with the multiphoton confocal microscope at consecutively deeper planes.
Figure 2
shows images captured from WT and Cav-1 KO mice at the surface and deeper levels of the plug. Optical sections were taken at 5-µm intervals until the fluorescence signal was undetectable. Note the similar levels of fluorescence outlining vessels at the surface (50-µm depth) in both WT and Cav-1 KO plugs. Although fluorescence levels became negligible at a depth of 180 µm in the Cav-1 KO plug, vessels were still apparent in the WT plug until the maximal depth obtainable with this technique, ie, 300 µm. Thus, vessel infiltration is clearly reduced in Cav-1 KO Matrigel plugs.
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By 2.5 weeks, histological analysis reveals the entire WT bFGF Matrigel plug to have undergone angiogenesis, as well as a later-forming adipogenic response, whereas Cav-1 KO plugs clearly showed a diminished angiogenic response (Figure 3, A and B)
. Importantly, Matrigel plugs not supplemented with bFGF failed to induce an angiogenic response in either WT or Cav-1 KO mice (Figure 3, A and B)
. Quantitative analysis of the bFGF-supplemented Matrigel plugs from Cav-1 KO mice reveals an almost twofold reduction in the number of vessels per field, as compared with plugs from WT mice (WT, 32.9 ± 2.3 versus KO, 17.4 ± 2.9; vessels/field; Figure 3C
, counted at a magnification of x20). Thus, the angiogenic process is significantly reduced in Cav-1 KO mice.
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bFGF has been shown to play an important role in angiogenesis during melanoma progression.20,21 Therefore, we used the well-characterized technique of exogenous tumor formation to examine if tumor angiogenesis is also negatively affected in Cav-1 KO mice.22 This approach has the benefit of excluding any effects that might result from the loss of Cav-1 in the tumor cells because Cav-1 has been identified as a tumor suppressor.23 To this end, B16-F10 melanoma cells (0.75 x 106 cells) were injected subcutaneously into the flanks of WT or Cav-1 KO mice. We chose to use B16-F10 cells as they are derived from C57BL/6 mice and, thus, are immunologically compatible with the C57BL/6 mice (WT and Cav-1 KO) used in this study.
Figure 4A
shows representative tumors removed from WT and Cav-1 KO mice 12 days after injection. Tumors grown in Cav-1 KO mice showed an overall reduction of 35% in tumor weight, as compared to WT controls (WT, 820 ± 110 versus KO, 528 ± 91, mg ± SEM; Figure 4B
). A corresponding decrease of 33% in tumor volume was also observed in Cav-1 KO mice versus WT controls (WT, 108.2 ± 10.7 versus KO, 71.3 ± 13.4, mm3 ± SEM; Figure 4C
).
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, counted at a magnification of x40). Endothelial Cells Derived from Cav-1 KO Mice Lack Caveolae and Form Incomplete/Poorly-Organized Nascent Capillaries
To assess the phenotypic behavior of WT and Cav-1 KO endothelial cells, the vessels that infiltrated exogenous tumors grown in WT and Cav-1 KO mice were examined by transmission electron microscopy. Importantly, the capillary endothelium of the exogenous tumor has its origin from pre-existing vessels within the mouse into which tumor cells were injected.
High-magnification views of nascent capillary endothelial cells show abundant caveolae (50 to 100 nm vesicles and invaginations) in endothelial cells derived from WT mice, as expected. However, Cav-1 KO endothelial cells show a complete ablation of caveolae formation (Figure 5A)
, in accordance with our previously published studies on lung endothelial cells.7
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. These results are consistent with the idea that Cav-1-null mice have defects in angiogenesis, as the nascent capillaries that they form within tumors are clearly morphologically incomplete or are very poorly organized. Examples of larger nascent capillaries are shown in Figure 5B
, whereas smaller nascent capillaries are shown in Figure 5C
. The Observed Angiogenesis Defect in Cav-1-Null Mice Is Specific for the Loss of Cav-1 Protein Expression and Is Not Related to a Loss of Cav-2 Protein Expression
Cav-1 deficiency in mice leads to an 95% reduction in Cav-2 protein levels, as Cav-1 protein expression is required to stabilize the Cav-2 protein product.7
Therefore, Cav-1-null mice are essentially deficient in both Cav-1 and Cav-2. To determine whether the defective angiogenesis phenotype seen in Cav-1-null mice is because of the loss of Cav-1 or Cav-2, we also examined angiogenesis in Cav-2-null mice17
using bFGF-supplemented Matrigel plugs.
Importantly, Figure 6
shows that Cav-2-null mice do not show any decreases in vessel density; instead, surprisingly, they show an increase in vessel density compared to WT. These results clearly indicate that loss of Cav-1, and not Cav-2, is responsible for the angiogenesis defect observed in Cav-1-null mice.
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Discussion |
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TopAbstractExperimental ProceduresResultsDiscussionReferences |
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Although Cav-1 KO mice demonstrate vascular hyperpermeability, it is most likely because of altered tight-junction function, as demonstrated by ultrastructural analysis of tight-junctions in the lung microvasculature.6 Therefore, it is possible that the intercellular hyperpermeability associated with Cav-1 loss is of a different nature and degree than that resulting from caveolae or vesiculo-vacuolar organelles intraendothelial passage, and is incommensurate with an angiogenic program. In addition, Cav-1 KO mice are hyperpermeable under baseline conditions, and it is not clear if basal hyperpermeability negatively affects the beginning stages of the angiogenic process. However, if caveolae and vesiculo-vacuolar organelles formation is a prerequisite for subsequent angiogenic phenomena, then loss of Cav-1 may in part explain the reduced angiogenesis observed in this study.
Cav-1 KO mice have increased basal levels of endothelial nitric oxide synthase (eNOS) activity, and nitric oxide has been proposed to contribute to VEGF-mediated angiogenesis.29,30 However, the angiogenic effects of bFGF has been shown to be independent of nitric oxide.30 Similarly, VEGF and bFGF have also been shown to differ in the integrins they use to mediate angiogenesis.31 It will be of great interest in the future to examine multiple angiogenic factors (including VEGF) within the Cav-1 KO background, to further define the role of Cav-1 in angiogenesis. Interestingly, a recent study shows the loss of caveolae through cholesterol depletion is associated with the inhibition of VEGF-mediated endothelial cell migration in vitro,32 suggesting a role for caveolae during the endothelial invasive response of angiogenesis.
There is abundant evidence that integrin signaling plays an important role in angiogenesis. For example, 
vß3 expression is markedly up-regulated on vascular cells in tumors.33
Disruption of vß3 ligation with antibodies or peptide antagonists inhibits blood vessel formation in angiogenesis assays,34-36
and specifically abolishes bFGF-mediated angiogenesis.31
Curiously, angiogenesis is enhanced in mice with a null mutation in the ß3 or ß3/ß5 integrin genes.37
Although an explanation that unifies these data awaits further investigation, they clearly show integrin involvement in the process of angiogenesis.
Cav-1 has been shown to co-immunoprecipitate with various integrin subunits.38
It is thought that Cav-1 may serve as a membrane adaptor that couples the integrin subunit to Fyn, which phosphorylates Shc, resulting in the downstream activation of the Ras-Erk pathway.38,39
It is thus possible that loss of Cav-1 affects this signaling cascade, and thereby disrupts the migration and subsequent differentiation phase of the angiogenic process.40
Cav-1 also co-immunoprecipitates with the glycolipid-anchored urokinase receptor (uPA-R).41 The formation of complexes with the uPAR may help to mediate the proteolysis necessary for invasion and migration, as well as, the nonproteolytic cell adhesion events during angiogenesis. It has been shown that uPA-R forms a complex with Cav-1 and the ß1 integrin, and loss of Cav-1 disrupts the uPA-R/integrin complex and focal adhesion formation. Interestingly, bFGF up-regulates uPA, the ligand for the uPA-R, mediating the migration of endothelial cells in the angiogenic process.42,43 In turn, integrins can serve to reciprocally facilitate bFGF receptor signaling.44 Blocking either bFGF or uPA activity is sufficient to inhibit angiogenesis.21,45,46 Thus, Cav-1 may act at multiple steps in the bFGF-uPAR-integrin-mediated angiogenic process.
We have previously reported alterations in endothelial cell-cell and cell-matrix adhesion in the lung vasculature of the Cav-1 KO mouse.6 Ultrastructural analysis in the present study shows a marked diminishment in caveolae and other caveolae-sized vesicular structures in exogenous tumors from Cav-1 KO mice. Tumors grown in Cav-1 KO mice have capillaries that are poorly formed and disorganized, as compared with capillaries formed within tumors grown in WT mice. This suggests that invading endothelial cells from the Cav-1 KO mouse have a delayed or diminished capacity to form a complete capillary structure. As previously reported, the endothelium of Cav-1 KO mice still contains some larger vesicular structures, but classically shaped and sized caveolae are absent in Cav-1 KO mice.8 As relatively sizeable exogenous tumors are still able to form in both WT and Cav-1 KO mice, the endothelial disruption in Cav-1 KO mice is not sufficient to eliminate all capillary formation, but clearly affects the kinetics of tumor growth. The morphological alterations observed in Cav-1 KO capillaries is in addition to the already abnormal nature of tumor blood vessels, as compared with the organization of the normal vasculature.47
Quantitation of vessels in the Matrigel plugs clearly shows that diminished angiogenesis is specific to the Cav-1 KO mouse. Surprisingly, Matrigel plugs implanted in Cav-2 KO mice showed an enhanced angiogenic response. These data argue that caveolar structures play an important role in angiogenesis, as Cav-2 KO mouse cells (including endothelia) still form normal caveolae through the homo-oligomerization of Cav-1.17 Thus, there may be important differences in the capacity of Cav-1 homo-oligomeric caveolae versus Cav-1/Cav-2 hetero-oligomeric caveolae to facilitate the process of angiogenesis.
We have previously shown using an in vitro adenoviral approach and cultured endothelial cells that down-regulation of Cav-1 markedly reduces endothelial cell tube formation, whereas overexpression of Cav-1 enhances the generation of endothelial tubes.11 These findings are consistent with the studies of Griffoni and colleagues12 who showed that Cav-1 anti-sense oligonucleotides strongly suppress endothelial tube formation in a three-dimensional fibrin gel angiogenesis assay. In addition, it was shown that Cav-1 anti-sense oligonucleotides also dramatically reduce vessel formation using the chorioallantoic membrane assay. Thus, our current studies using Cav-1 KO mice and in vivo assays of angiogenesis directly support these earlier in vitro studies.
It is of interest that in Cav-1 KO mice, bFGF-supplemented Matrigel plugs showed marked cellular proliferation or hypercellularity directly adjacent to the plug. This is consistent with our previous work indicating a role for Cav-1 as an inhibitor of cellular proliferation.14,23
In fact, one of the major phenotypes of the Cav-1 KO mouse is the hyperproliferation of the lung parenchymal and primordial endothelial cells.7,8
Perhaps bFGF-supplemented Matrigel plugs illicit a similar hyperproliferative response in the Cav-1 KO cells in the periplug region. This hypothesis is consistent with our previous interpretations of in vitro experiments in which we speculated that down-regulation of Cav-1 is an important aspect of the proliferative component of angiogenesis, whereas up-regulation of Cav-1 facilitates differentiation later in the angiogenic process. These data also support a role for Cav-1 in the migratory and/or differentiation phases of angiogenesis. Consistent with this notion, we show here that vessel infiltration and density are significantly reduced by 35 to 50% in Cav-1 KO mice using two different in vivo angiogenesis assays (Matrigel plugs and exogenous tumor formation).
We have recently shown that Cav-1 KO mice are clearly more susceptible to tumor formation/cell transformation induced either by treatment with chemical carcinogens (DMBA) or by breeding with tumor-prone animals (MMTV-PyMT).48,49 Despite the dramatic tumor suppressor effects we observed, it is important to note that these tumor suppressor effects may be underestimated due to the concomitant defects in angiogenesis in Cav-1 KO mice that we describe here.
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Acknowledgements |
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Footnotes |
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Supported by grants from the National Institutes of Health, the Muscular Dystrophy Association, the American Heart Association, and the Breast Cancer Alliance, as well as a Hirschl/Weil-Caulier Career Scientist Award (all to M. P. L.); and by a National Institutes of Health Medical Scientist Training Grant (T32-GM07288; S. E. W. and T. M. W.).
Accepted for publication February 28, 2003.
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