Involvement of Endothelial CD44 during in Vivo Angiogenesis

Abstract

CD44, a cell-surface receptor for hyaluronan, has been implicated in endothelial cell functions, but its role in the formation of blood vessels in vivo has not been established. In CD44-null mice, vascularization of Matrigel implants and tumor and wound angiogenesis were inhibited. Leukocyte accumulation during tumor growth and wound healing in wild-type and CD44-null mice were comparable, and reconstitution of CD44-null mice with wild-type bone marrow did not restore the wild-type phenotype, suggesting that impairments in angiogenesis in CD44-deficient mice are due to the loss of endothelial CD44. Although the cell proliferation, survival, and wound-induced migration of CD44-null endothelial cells were intact, these cells were impaired in their in vitro ability to form tubes. Nascent vessels in Matrigel implants from CD44-null mice demonstrated irregular luminal surfaces characterized by retracted cells and thinned endothelia. Further, an anti-CD44 antibody that disrupted in vitro tube formation induced hemorrhage around Matrigel implants, suggesting that antagonism of endothelial CD44 undermined the integrity of the endothelium of nascent vessels. These data establish a role for CD44 during in vivo angiogenesis and suggest that CD44 may contribute to the organization and/or stability of developing endothelial tubular networks. 2). HA has also been implicated in the formation of vessels, but its effects on in vivo angiogenesis and endothelial cell (EC) function are complex and depend on HA concentration and molecular size.3 High molecular weight HA (at concentrations of Ͼ100 g/ml) inhibits EC proliferation and disrupts confluent endothelial monolayers. 4 These findings are consistent with the fact that avascular regions in chick embryo limb buds are rich in native high molecular weight HA and that expression of this form of HA in normally vascular areas results in decreased vascularity. 5 In contrast, low molecular weight HA stimulates EC proliferation, 4,6 wound-induced migration, 6 in vitro endothelial tube formation, 7 and neovascularization in chick chorioallantoic membranes 8 and cutaneous wounds. 9,10 HA mediates its biological effects through binding interactions with specific cell-associated receptors.11 A number of HA-binding proteins (so-called hyaladherins) have been identified, with CD44 and Receptor for HAMediated Motility (RHAMM) being the two best characterized cell-surface receptors for HA.2 Although several other binding interactions for CD44 and RHAMM have been reported, 12,13 currently their interactions with HA appear to be the ones most likely to directly activate intracellular signals required to stimulate processes relevant to angiogenesis.14 With respect to EC functions, previous studies have implicated CD44 in EC proliferation, migration, and adhesion to HA; RHAMM in EC motility; and both receptors in EC tube formation. [15][16][17][18][19][20][21][22] Although there is evidence for the activity of RHAMM during in vivo angiogenesis, 16 the involvement of CD44 in the formation of blood v...

CD44 Is Critically Involved in Infarct Healing by Regulating the Inflammatory and Fibrotic Response

“…Diverse cellular functions have been attributed to CD44, including involvement in leukocyte chemotaxis and activation (23), clearance of apoptotic cells and matrix fragments (6,24), resolution of chronic inflammation (6), regulation of fibrous tissue deposition (11), and angiogenesis (25). The present study reports the first evidence that CD44 plays an essential role in infarct healing and regulates postinfarction cardiac remodeling.…”

Hyperproduction of Hyaluronan in Neu-Induced Mammary Tumor Accelerates Angiogenesis through Stromal Cell Recruitment

“…Recently, Cao et al 41 demonstrated the involvement of endothelial CD44 during in vivo angiogenesis. We therefore used the Matrigel plug assay to evaluate in vivo angiogenesis in CD44-null mice and found that the angiogenic response to HA-versican aggregates persisted even in the absence of CD44 (data not shown).…”

A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis

“…17 bFGF and VEGF, 2 important angiogenic factors, up-regulate CD44 on ECs in vivo, and targeting of CD44 by specific antibodies leads to EC killing. 32 CD44-specific antibodies repress EC proliferation and capillary formation in fibrin matrix.…”

“…Their extracellular part is required for c-Met activation, whereas the cytoplasmic domain of CD44 recruits ERM proteins (Ezrin-Radixin-Moesin) that bind the cytoskeleton and promote activation of Ras by its guanidine exchange factor (GEF) son of sevenless (SOS). 16 Because HGF and c-Met are also important in angiogenesis and because angiogenesis is impaired in CD44 null mice, 17 we have examined whether HGF, c-Met, and the CD44v6 isoform also cooperate in ECs. A CD44v6-specific peptide as well as a CD44v6 antibody can indeed block c-Met activation on ECs and HGFinduced migration and tubular vessel formation by ECs is impaired.…”