How Do Mesangial and Endothelial Cells Form the Glomerular Tuft?
Michael R. Vaughan*, and
Susan E. Quaggin*,,
* Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Institute of Medical Science, and Department of Medicine and Division of Nephrology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada; and Division of Nephrology, University of Washington, Seattle, Washington
Correspondence: Dr. Susan E. Quaggin, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada. Phone: 416-586-4800; Fax: 416-586-8588; E-mail: quaggin{at}mshri.on.ca
The glomerular capillary tuft is a highly intricate and specializedmicrovascular bed that filters plasma water and solute to formurine. The mature glomerulus contains four cell types: Parietalepithelial cells that form Bowman's capsule, podocytes thatcover the outermost layer of the glomerular filtration barrier,glycocalyx-coated fenestrated endothelial cells that are indirect contact with blood, and mesangial cells that sit betweenthe capillary loops. Filtration begins only after the influxand organization of endothelial and mesangial cells in the developingglomerulus. Tightly coordinated movement and cross-talk betweenthese cell types is required for the formation of a functionalglomerular filtration barrier, and disruption of these processeshas devastating consequences for early life. Current conceptsof the role of mesangial and endothelial cells in formationof the capillary tuft are reviewed here.
Glomerular morphogenesis proceeds through several well-definedstages in embryonic development, beginning first as a renalvesicle, followed by the comma-shaped body, S-shaped body, acapillary loop stage, and then the mature glomerulus (Figure 1).The epithelial components of the glomerulus—the parietalepithelial cells and podocytes—derive from the metanephricmesenchyme. These mesenchymal cells adjacent and inferior tothe tips of the branching ureteric bud begin to condense at11.5 d post coitum in the mouse or after 5 wk of gestation inhumans.1,2 This collection of cells is known as the pretubularaggregate (Figure 1). In response to inductive cues from theureteric bud and surrounding stroma, the aggregates undergoa mesenchymal-to-epithelial transition forming the renal vesicleand then the comma-shaped body.3–6 The glomerulus developsfrom the most proximal end of the renal vesicle that is farthestfrom the bud tip. Distinct cell types in the glomerulus arefirst identified in the S-shaped stage, where presumptive podocytesappear as a layer of columnar-shaped epithelial cells. A vascularcleft develops and separates the presumptive podocyte layerfrom more distal cells that will form the proximal tubule (Figure 1).It is into this cleft that vascular endothelial cells migratefollowed by mesangial cells.7
Figure 1. Migration of endothelial cells into the developing glomerular tuft. (Top) An embryonic day 12.5 mouse metanephros is outlined in black. Endothelial cells express a VEGFR2-GFP transgene and stain brown. The glomerulus develops from a pretubular aggregate (agg) that forms immediately adjacent and below the tips of the ureteric buds (ub). These aggregates derive from metanephric mesenchymal cells that have been induced to condense and epithelialize by signals produced in the ureteric buds. (Middle and Bottom) VEGFR2-positive cells are seen to "hug" the developing comma-shaped–stage nephron. The s-shaped stage is defined by the presence of a layer of podocyte precursors (presumptive podocytes) (po) and a vascular cleft. Endothelial cells seem to be streaming into this cleft from the Metanephric mesenchyme (MM). At the capillary loop stage, pockets of endothelial cells sit right next to the podocytes, and mesangial cells are soon found inside a single capillary loop. By the maturing stage, capillary lumens are beginning to form and a large population of mesangial cells is present. Schematic diagrams of each developmental stage are shown above the photomicrographs. Podocytes have been digitally colorized for identification (pink). Adapted from Saxen.1 pa, parietal epithelial cell; po, podocyte; me, mesangial cell; cap, capillary loop.
Individual endothelial progenitors, or "angioblasts," are easilyidentified in the developing kidney because they express typicalvascular markers such as vascular endothelial growth factorreceptor 2/Flk1 (VEGFR2). At the comma-shaped stage, these angioblastshug the outside of the developing nephron and then "stream"into the vascular cleft (Figure 1). Much earlier in development,angioblasts and renal progenitor cells reside together in aregion known as the aortogonadal mesonephros, where early hematopoiesistakes place. In lower organisms, hematopoiesis continues tooccur in the adult kidney, as in the pronephros of zebrafish.The mammalian kidney develops in three successive stages knownas the pronephros, the mesonephros, and the metanephros; onlythe metanephros gives rise to the definitive adult kidney, andit no longer functions as a site of hematopoiesis. It is stilldebated whether angioblasts migrate into the developing metanephrosor arise in situ from a common progenitor. This is an interestingquestion given the close geographic and functional relationshipthat these progenitors exhibit during evolution. Experimentaldata regarding the origin of these angioblasts within the metanephrosis discussed in a later section.
The movement of endothelial progenitors into the vascular cleftdepends on the expression of angiogenic factors such as VEGF-Aby presumptive podocytes.8,9 Once inside the developing glomerulus,endothelial cells proliferate in situ and aggregate to formthe first capillary loops. Rather than using a process called"sprouting angiogenesis," whereby a vessel with a lumen invadesa tissue, glomerular precapillary cords form as a result ofhomotypic interactions between adjacent endothelial cells. Initially,these capillary cords lack a lumen that develops only laterthrough selective apoptosis of endothelial cell subsets.10 Thisprocess of lumenation is dependent on TGF-β signaling.11As glomeruli mature, the cords become lumenal and the initialcapillary loop divides into six to eight loops. Residual endothelialcells differentiate, becoming flattened, and acquire a fenestratedmorphology. The fenestrae are pores lined by plasma membranethat pass through the endothelial cell. Unlike other fenestratedendothelial cells found in pituitary and endocrine organs, themajority of glomerular fenestrae in adult kidneys lack typicaldiaphragms associated with the PV1 protein.12 However, theyare bridged by an electron-dense complex that is referred toby some but not all groups as a "diaphragm."13,14 Exactly howthis diaphragm forms during development is unclear, but it isthought to arise from proteoglycans and other proteins producedby differentiating glomerular endothelial cells. Disruptionof this barrier through injection of enzymes (hyaluronidase,heparinase, and chondroitinase) results in changes in glomerularpermeability.15
After the initial influx of endothelial cells, mesangial cellsenter the glomerulus, forming a stalk, or "core," of cells aroundthe early, single capillary loop. During nephrogenesis, thesemesangial cells are identified by their expression of variousmarkers, including Thy1.1 (in rats), desmin, -smooth muscleactin (-SMA), and the PDGF beta receptor (PDGFRβ) (Figure 2).16,17The subsequent looping of glomerular capillaries will not proceedin the absence of mesangial cells or in glomeruli with defectsin basement membrane that prevent adherence of mesangial cells.17,18This demonstrates that mesangial cells play a key morphogeneticrole in forming the capillary tuft. In the prevailing model,mesangial cells split a single vessel loop that extends intoBowman's space by forming a capillary tuft with multiple, parallelbranches known as "intussusceptive" splitting of vessels (Figure 3).Mesangial cells also provide a mechanical function for preservationof capillary loops, as loss of mesangial cells (known as mesangiolysis)results in dilation of the glomerular capillary loops. Althoughit is clear that mesangial cells are required for this looping,the specific mesangial factors guiding such events have notbeen identified.
Figure 2. Mesangial cells in the early glomerular tuft. Mesangial cells (green) express desmin, whereas podocytes (red) express WT1. Vascular -SMA, another marker of mesangial cells, is expressed after desmin. Figure courtesy of J. Miner, PhD, Washington University, St. Louis.
Figure 3. Intussusceptive splitting of vessels by mesangial cells. PDGF-B is produced by glomerular endothelial cells and promotes recruitment of mesangial cells that express the PDGFRβ. Mesangial cells split a single vessel loop that extends into Bowman's space into a capillary tuft with multiple, parallel branches. Figure courtesy of C. Betsholtz, PhD, Karolinska Institute, Stockholm, Sweden.
Conflicting views exist regarding the origin of glomerular endothelialand mesangial cells. Although the metanephric mesenchyme containsVEGFR-2–positive angioblasts from early stages of development,cross-species transplantation studies suggest that extrarenalcells also contribute to glomerular vasculature. This is perhapsnot surprising, given the ability of donor endothelial cellsto "hook up" with host vasculature under very artificial circumstances(Helmutt Augustin, DVM, PhD, Joint Research Division VascularBiology of the Medical Faculty Mannheim, University of Heidelbergand the German Cancer Research Center, Germany, personal communication,March 2007); for example, human endothelial cells transplantedunder the skin of the mouse can form functional vessels thatconnect to murine vessels. What is also intriguing about kidneytransplantation experiments is the variability in host versusdonor contribution, which can range from only a few cells tothe majority of cells.19–23 The factors that permit hostcells to contribute more efficiently to glomerular vasculaturethan donor cells under certain circumstances are not known butmay depend on the location of the transplant site, the fetalage of the transplanted kidney, or other interspecies differences.Local environment also seems more important for vasculogenesisin the kidney than in some other organs. Although many partsof the embryonic kidney grow and develop in explant cultures(e.g., branching of the ureteric bud, early nephron formation),the renal vasculature never develops ex vivo.24 This is in strikingcontrast to the strong vascular development and migration seenin heterologous mesonephric-gonad explants. The reasons forthese differences are not understood.25
Similar to endothelial cells, the origin of the mesangial cellprecursors remains a mystery, although cells from within themetanephric mesenchyme always contribute to the mesangium incross-species transplant experiments.19,20 Mesangial molecularmarkers have also been observed within developing glomerulararterioles,17 confirmed by lineage tagging experiments in transgenicmice that express Cre-recombinase from the endogenous reninlocus.26 Growth factors such as PDGF-B that are produced byglomerular endothelial cells are major signals for mesangialcell recruitment and is discussed next. Interestingly, the factthat mesangial cells appear after the influx of endothelialcells suggests that the endothelial cells may control glomerulardevelopment through factors such as PDGF-B.
Alternative sources for mesangial cells have been proposed bywork in models of glomerular disease. Mesangiolysis, the mostextreme form of mesangial damage, results in loss of mesangialcells, destruction of the mesangial cell matrix, and ballooningof the capillary loop. In the anti-Thy1.1 model of mesangiolysis,the mesangial compartment is regenerated by cells recruitedfrom the juxtaglomerular apparatus, also referred to as theextraglomerular mesangium.27 Other animal studies demonstratethat bone marrow–derived cells can replenish mesangialcells.28 For investigation of the contribution of bone marrow–derivedcells with mesangiolysis, crude preparations of donor bone marrowcells from rats that express enhanced green fluorescence proteinin all tissues were transplanted into wild-type recipients.The wild-type rats with "fluorescence-tagged" bone marrow werethen given anti-Thy1 antibody to induce mesangiolysis. Aftermesangial injury, tagged bone marrow cells contributed up to7% of the reconstituted population of mesangial cells. Morerecently, clones of purified hematopoietic bone marrow stemcells (defined as lin–/Sca1+/c-kit+/CD34–) expandedex vivo were found on transplantation to populate the mesangium.29Similar to native mesangial cells, these reconstituted mesangialcells responded to angiotensin II, suggesting that they arefunctional and not simply trapped bone marrow–derivedcells. Male-to-male transplant studies revealed a single y-chromosomein transplanted mesangial cells, thereby demonstrating thatthese cells were not merely the result of cell fusion.
GENETIC BASIS OF ENDOTHELIAL AND MESANGIAL CELL RECRUITMENT
Gene targeting experiments in mice and genetic studies in humansdemonstrate an essential role for molecular cross-talk betweencells in the glomerular compartments during the formation ofthe tuft (Table 1). The best understood examples of this cross-talkinvolve growth factor signaling pathways, although mutationsin a number of genes expressed by podocytes (e.g., transcriptionfactors) also have profound effects on both glomerular endothelialand mesangial cells.
Table 1. Genes involved in endothelial and mesangial recruitment and formation of the capillary tuft
Podocyte and Mesangial Cell–Derived Cues in Vascular Signaling Pathways
During glomerular development, podocytes produce a number ofangiogenic growth factors, including VEGF-A, VEGF-C, angiopoietin-1,and ephrinB2, whereas adjacent endothelial cells express theircognate receptors.9,30–33 Deletion or overexpression ofVEGF-A selectively within podocytes, for example, results indramatic defects in endothelial cell in-growth, proliferation,survival, and differentiation in glomeruli.9 Capillary ghostsare observed in glomeruli deficient in VEGF-A (Figure 4), andprogressive decreases in the levels of VEGF-A lead to more profounddefects in adjacent endothelia, emphasizing the importance ofthis paracrine signaling pathway.
Figure 4. Transmission electron micrographs of the glomerular filtration barrier. Wild-type mouse (left) and transgenic mouse (right) with the latter showing selective deletion of VEGF-A from the podocytes (po). Podocytes are seen in both, but the endothelium (en) is entirely missing from the null mouse, leaving a "capillary ghost." Immunostaining for WT1 (podocytes [green]) and platelet-endothelial cell adhesion molecule (endothelial cells [red]) confirms the absence of capillary wall or endothelium in VEGF-A null mouse. (Reproduced with permission from JCI.)
Although ephrinB2 is seen at the S-shaped stage in developingpodocytes, its expression rapidly switches to the endothelialand mesangial compartments. Deletion of ephrinB2 from mousemesangial cells at 14.5 d post coitum results in arrested glomerulardevelopment with a reduced number of capillary loops.34 Geneticdeletions of other vascular growth factor ligands are not yetknown because standard null mice for various vascular growthfactor receptors all produce lethality during embryogenesisthat precludes analysis of kidney phenotypes. However, it ispredicted that these vascular growth factors also play importantroles in glomerular endothelial cell proliferation and remodelingas in other vascular beds; for example, standard null mice forVEGFR2/Flk1 fail to make intact blood vessels as a result ofloss of endothelial cells, whereas null mice for VEGFR1/Flt1(the decoy receptor for VEGFR1) exhibit overgrowth of endothelialcells that prevents proper modeling of the vasculature and deathof the fetus. Because both of these tyrosine kinase receptorsfor VEGF-A are also expressed in all endothelial cells of thekidney, it is likely that they are required for growth and remodelingof the renal vasculature. Tie1, another vascular tyrosine kinasereceptor, may play a unique role in developing glomerular endothelia.Tie1 null mice die during embryonic life as a result of lossof integrity of the endothelium followed by hemorrhage. To overcomethis early defect, chimeric mice were generated from embryonicstem cells that lacked a functional vascular receptor tyrosinekinase Tie1. Tie1 null cells from this chimera contributed tothe endothelium within various vascular beds but were unableto contribute to the glomerular vasculature, suggesting an importantand possibly unique role for Tie 1 in the glomerulus.35 Interestingly,no ligand for Tie1 has yet been identified, so whether one isproduced by glomerular cells is unclear.
The Notch signaling pathway is another key regulator of vasculardevelopment. The vessels in developing mouse retina respondto levels of VEGF-A through specialized "tip" cells whose fateis determined by -like 4-Notch1 signaling.36 Members of theNotch signaling pathway are dynamically expressed during glomerulardevelopment,37 and glomeruli from mice that are homozygous fora hypomorphic Notch2 allele arrest at the capillary loop stageor form defective glomeruli with aneurysmal dilation of thecapillaries. These glomeruli consist of a disorganized clumpof cells that express some podocyte markers but lack mesangialand endothelial cell markers. Levels of VEGF-A are reduced inthe glomeruli of these mice, which may explain the defect inendothelial and mesangial cell recruitment.
Glomerular endothelial cells exhibit shared but also uniqueproperties with other vascular endothelia. It is perhaps notsurprising that macromolecules such as albumin are primarilyprevented from crossing the endothelium (although this is anarea of controversy), because endothelium throughout the bodypossesses this property. Rather, it is the capacity of the glomerularendothelia to withstand or provide high permeability to waterand small solutes that is so unusual. This is accomplished inpart by the presence of fenestrations. Glomerular fenestrationshave many similarities to fenestrations found in endothelialcells of other organs, except for the absence of diaphragms.Perhaps the most similar endothelial cells are found in theliver sinusoids, which also lack diaphragms.
What regulates formation of the fenestrations? Although VEGFproduction by podocytes is necessary for maintenance of fenestrationsas shown in the podocyte-selective null models, it is clearlyinsufficient. Several groups are actively looking for glomerulargenes and/or profiles of glomerular genes that dictate the uniqueproperties of these endothelial cells. To date, a number ofinteresting candidate genes (e.g., chloride CN5, EHD3) thatare expressed selectively in glomerular endothelial cells havebeen identified by a serial analysis of gene expression (SAGE)or array analysis; however, their roles in glomerular developmentin vivo are not yet known.38,39 Identification of these uniquetranscripts should provide important clues to specialized featuresof the endothelium and ultimately will allow us to develop usefulgenetic tools to manipulate gene expression selectively withinthe glomerular endothelium. This is relevant because many glomerulardiseases are thought to result from damage to the glomerularendothelium; this is not contested in diseases such as thromboticmicroangiopathy but is debated in diseases such as diabeticnephropathy. The generation of glomerular endothelial-specificCre mouse lines will permit researchers to address these questionsgenetically. These mouse tools will also permit researchersto dissect the importance of the glomerular endothelium in generatingand maintaining the permselective properties of the glomerularfiltration barrier, which is still hotly debated.
Growth Factors and Endothelial-Derived Cues
As outlined, podocytes and mesangial cells provide molecularsignals to the developing glomerular vasculature. In a reciprocalmanner, glomerular capillaries deliver blood, nutrients, andmechanical and molecular signals to adjacent partners in thetuft. The first example of this cross-talk during glomerulardevelopment was provided by the dramatic phenotype in PDGF-Band PDGFRβ null mice.17,40 In the glomerulus, endothelialcells express PDGF-B, whereas mesangial cells express its receptor.In PDGFRβ null mice, capillary tufts fail to develop andcompletely lack mesangial cells. Ultrastructurally, the glomeruliin these null mice contain only a few distended or balloonedcapillary loops in which the basement membrane and overlyingpodocytes are juxtaposed against Bowman's capsule, with a lossof Bowman's space (Figure 5). Endothelial cells deleted conditionallyof PDGF-B were shown to have a similar ballooned capillary phenotype,confirming the presence of a paracrine signaling loop from theglomerular endothelia to mesangium.41
Figure 5. Glomerular phenotype in PDGFR-β receptor null mice. Mesangial cells do not migrate into the capillary tuft, resulting in a single balloon-like capillary loop. (Figure 5 courtesy of C. Betsholtz.)
More recently, deletion of the G protein–coupled receptor,GPR4, from mice resulted in glomeruli with fewer mesangial cells.Although tortuous and dilated blood vessels with hemorrhagingare found throughout the GPR4 null neonates, the glomerularcapillary tuft appears well formed. Interestingly, vascular-SMA–positive cells, a late marker of mesangial differentiation,were reduced.42 Given the fairly normal-appearing glomerulararchitecture, it will be important to know whether earlier markersof mesangial cell differentiation are expressed (e.g., PDGFRβ,desmin) and whether the mesangial cell lineage is present butremains undifferentiated. GPR4 is expressed in the vasculatureand kidney and functions as an extracellular pH sensor, suggestingthat physiologic changes within the vascular microenvironmentare determinants of maturation.
Is differentiation of a mature glomerular endothelium also requiredfor terminal differentiation of the podocyte lineage? The dataare conflicting. Studies from zebrafish show that endothelialcells are not required for determination of the podocyte celllineage because podocytes develop in "cloche" mutants that haveno endothelia.43 However, differentiation of specialized podocytefeatures, such as slit diaphragms, was not described in thesemutants. It seems likely that endothelial cells produce signalsthat are required for maintenance, survival, and differentiationof podocytes. In podocyte-selective VEGF-A null mice, althoughpodocytes are present, ultrastructural abnormalities such asabnormal slit diaphragms are present as well (Figure 4).
Transcription Factors, Integrins, and Matrix Proteins
Several other genes expressed by podocytes are required forproper formation of glomerular capillary loops and mesangium.These genes encode 3 integrin and four transcription factors:Pod1 (Tcf21/capsulin/epicardin), Lmx1b, Foxc2, and Kreisler.39,44–47Glomeruli from null mice for each of these genes have reducednumbers and complexity of capillary loops, defects in mesangialcell recruitment, and podocyte abnormalities (Figure 6). Microarrayand candidate gene analysis shows that levels of type IV collagen(a component of the glomerular basement membrane [GBM]) andpodocin are reduced in glomeruli from mice lacking any of thetranscription factors listed.39,48–51 Given the similarrenal phenotypes and expression profiles, these genes may regulatethe same transcriptional pathways.
Figure 6. Glomeruli from Pod1 and Foxc2 null mice. Glomeruli from wild-type (left) or null mice (right). Note the dilated capillary loop(s) and abnormal clump of mesangial cells (me) in the glomeruli from null mice. FoxC2 photomicrographs courtesy of Minoru Takemoto, MD, PhD, Department of Clinical Cell \E Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
Null mice have also demonstrated that matrix proteins in theGBM, such as laminins, are critical for glomerular maturation.Laminin 5 null embryos show extrusion of endothelial and mesangialcells from glomeruli that appear constricted with a completeabsence of vasculature.52 The developmental switch between lamininchains in the GBM, from 1 to 5, is required for adhesion ofmesangial cells to the basement membrane and subsequent loopingof glomerular capillaries.18
Human Genetic Mutations that Disrupt the Capillary Tuft
Diffuse mesangial sclerosis is a serious glomerular lesion usuallyresulting in ESRD by age 5 in humans. Pathologic analysis ofglomeruli from patients with this form of sclerosis suggestsa major defect in glomerular development. Capillary loops arereduced in number, and persistence or re-expression of -SMA,a marker of early mesangial cell differentiation, is seen. Failureof isoform switching of the VEGF-A gene—from the 165 tothe 165β isoform—has also been noted in glomerulifrom these patients.53 Three genetic mutations have been identifiedin sporadic or inherited forms of this disease. The first isfound in patients with Denys-Drash syndrome, a disorder characterizedby gonadal and renal dysgenesis that results from a mutationin the Wilms’ tumor suppressor gene (WT1), another transcriptionfactor expressed by podocytes; the second is found in Piersonsyndrome, which is caused by mutations in the GBM protein LAMB254;and, more recently, the third is found in truncating mutationsin the phospholipase epsilon C1 enzyme, which result in a heritableautosomal recessive form of diffuse mesangial sclerosis.55 Micethat overexpress the Denys-Drash mutant WT1 allele exhibit defectsin glomerular developmental with fewer capillary loops, anda knockdown of Plce1 in zebrafish results in developmental arrestof the single midline glomerulus, fusion of the foot processes,and edema.55,56 How mesangial sclerosis results from these geneticdefects is not entirely clear, but given that within the glomerulus,both of these genes are most highly expressed by podocytes,it is likely that altered cross-talk plays a role.
Glomerulogenesis provides important clues into glomerular functionin health and disease. At the core of the glomerulus is a complexstructure known as the capillary tuft that consists of invaginationsin the basement membrane surrounded by podocytes and endothelialand mesangial cells. Gene-targeting studies in mice and humangenetic studies provide molecular footholds into some of thekey pathways involved in capillary tuft development; these includeVEGF signaling, PDGF-B signaling, and enzymes such as PLCe1.Importantly, these studies provide a new understanding aboutcross-talk among the resident cells of the glomerulus (Figure 7).However, it is clear that many genes and pathways that willhelp to define the unique properties of the glomerular microvasculature,which in turn is required for formation of the urinary filtrate,remain to be uncovered. As additional pathways are described,they will provide potential avenues for therapeutic intervention.
Figure 7. Signaling pathways of capillary tuft development. The resident cells of the capillary tuft (podocyte, endothelial, and mesangial cells) each play critical roles in capillary tuft development. The development of the tuft is influenced by cellular cross-talk (solid arrows) and through various genes, transcription factors, and growth factors. These factors affect different aspects of capillary tuft development as noted by the dashed arrows.
This work was funded by a Kidney Foundation of Canada grantand Canadian Institutes of Health Research (CIHR) grants MOP-62931and MOP-77756 to S.E.Q. and National Institutes of Health grantsF32 DK070434 and K08DK076970 to M.V.
We thank Dragana Vukasovic for expert secretarial assistance.S.E.Q. is the recipient of a Canada Research Chair, Tier II,and a Premier of Ontario Research Excellence Award.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Abstract
OVERVIEW OF TUFT EMBRYOLOGY
-smooth muscle actin (
-like 4-Notch1 signaling.36 Members of the Notch signaling pathway are dynamically expressed during glomerular development,37 and glomeruli from mice that are homozygous for a hypomorphic Notch2 allele arrest at the capillary loop stage or form defective glomeruli with aneurysmal dilation of the capillaries. These glomeruli consist of a disorganized clump of cells that express some podocyte markers but lack mesangial and endothelial cell markers. Levels of VEGF-A are reduced in the glomeruli of these mice, which may explain the defect in endothelial and mesangial cell recruitment. 
