Reply from the Authors

Abstract

Braet and Soon question the conclusions we have drawn in a recent review1.Ballermann B.J. Glomerular endothelial cell differentiation.Kidney Int. 2005; 67: 1668-1671Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar about the relationship between caveolae and fenestrae in glomerular endothelium. They suggest that we were too hasty in stating that fenestrae do not represent fused caveolae. There is little doubt about the dynamic nature of fenestrae. Work with liver sinusoidal endothelial cells is particularly interesting because these cells retain very nice sieve plate structures in culture which can change rapidly by alterations in actin microfilament dynamics2.Braet F. Wisse E. Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: A review.Comp Hepatol. 2002; 1: 1Crossref PubMed Scopus (486) Google Scholar. Also, VEGF-A can induce endothelial fenestration. Conversely, interference with VEGF-A function in renal glomeruli, for instance, in preeclampsia3.Maynard S.E. Min J.Y. Merchan J. et al.Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.J Clin Invest. 2003; 111: 649-658Crossref PubMed Scopus (2873) Google Scholar or with podocyte VEGF-A haploinsufficiency4.Eremina V. Sood M. Haigh J. et al.Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases.J Clin Invest. 2003; 111: 707-716Crossref PubMed Scopus (996) Google Scholar leads to an absence of glomerular fenestrae. Finally, VEGF-A seems to induce caveolin-1-containing vesicles to fuse and to form transendothelial cell channels5.Vasile E. Qu H. Dvorak H.F. et al.Caveolae and vesiculo-vacuolar organelles in bovine capillary endothelial cells cultured with VPF/VEGF on floating Matrigel-collagen gels.J Histochem Cytochem. 1999; 47: 159-167Crossref PubMed Scopus (67) Google Scholar,6.Yokomori H. Oda M. Yoshimura K. et al.Vascular endothelial growth factor increases fenestral permeability in hepatic sinusoidal endothelial cells.Liver Int. 2003; 23: 467-475Crossref PubMed Scopus (73) Google Scholar. Such circumstantial evidence has suggested that fenestrae represent fused caveolae. However, in caveolin-1-deficient mice known to lack caveolae altogether7.Razani B. Engelman J.A. Wang X.B. et al.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, we found glomerular endothelium with fenestrae that were normal in size and density, even though no caveolin-1 and no caveolae were observed at all8.Sorensson J. Fierlbeck W. Heider T. et al.Glomerular endothelial fenestrae in vivo are not formed from caveolae.J Am Soc Nephrol. 2002; 13: 2639-2647Crossref PubMed Scopus (63) Google Scholar. In normal rat glomeruli examined for caveolin-1 localization by immunogold electron microscopy, fenestrated portions of glomerular endothelium were completely devoid of caveolin-1, similar to the report by Esser et al9.Esser S. Wolburg K. Wolburg H. et al.Vascular endothelial growth factor induces endothelial fenestrations in vitro.J Cell Biol. 1998; 140: 947-959Crossref PubMed Scopus (528) Google Scholar for the choroid plexus endothelium. Now, our experiments leave open the possibility that fenestrae in other vascular beds could represent fused caveolae, and that caveolar precursor vesicles lacking caveolin-1 could fuse to form fenestrae. But if caveolae are defined as specialized plasma membrane invaginations stabilized by caveolins, then our findings in caveolin-deficient mice seem to prove that fenestrae in glomerular endothelium cannot represent fused caveolae.