Loss of PECAM-1 Function Impairs Alveolarization

Abstract

The final stage of lung development in humans and rodents occurs principally after birth and involves the partitioning of the large primary saccules into smaller air spaces by the inward protrusion of septae derived from the walls of the saccules. Several observations in animal models implicate angiogenesis as critical to this process of alveolarization, but all anti-angiogenic treatments examined to date have resulted in endothelial cell (EC) death. We therefore targeted the function of platelet endothelial cell adhesion molecule, (PECAM-1), an EC surface molecule that promotes EC migration and has been implicated in in vivo angiogenesis. Administration of an anti-PECAM-1 antibody that inhibits EC migration, but not proliferation or survival in vitro, disrupted normal alveolar septation in neonatal rat pups without reducing EC content. Threedimensional reconstruction of lungs showed that pups treated with a blocking PECAM-1 antibody had remodeling of more proximal branches resulting in large tubular airways. Subsequent studies in PECAM-1-null mice confirmed that the absence of PECAM-1 impaired murine alveolarization, without affecting EC content, proliferation, or survival. Further, cell migration was reduced in lung endothelial cells isolated from these mice. These data suggest that the loss of PECAM-1 function compromises postnatal lung development and provide evidence that inhibition of EC function, in contrast to a loss of viable EC, inhibits alveolarization.

The Hematopoietic Chemokine CXCL12 Promotes Integration of Human Endothelial Colony Forming Cell–Derived Cells into Immature Vessel Networks

“…CD31 or PECAM-1 is a 130-kDa member of the Ig superfamily, which is highly expressed on endothelial cells in vitro and in vivo [48]. Although studies in mice have demonstrated that CD31 deficiency can be compensated by CD31-independent pathways during development [49], other research, which is consistent with our studies, has shown that CD31 antibodies or deficiency can block endothelial-endothelial interactions and the formation of endothelial tubules in Matrigel assays in vitro, as well as angiogenesis in in vivo murine models [48,50,51]. CD31/ PECAM-1 on endothelial cells also contributes to vascular barrier integrity [52] and arteriogenesis [53], to endothelial cell function required for alveolarization [50], and to enhanced retinal vascular density in postnatal mice when comparisons are made with PECAM-1-deficient mice [54].…”

Angiogenesis in Platelet Endothelial Cell Adhesion Molecule-1-Null Mice

“…These findings are similar to what was observed for murine postnatal lung development, where lung alveolarization was delayed in the PECAM-1-deficient mice (due to presumed impairments in angiogenesis) but had substantially recovered by the time the mice reached adulthood. 26 These data further implicate PE-CAM-1 in postnatal vascular developmental processes such as those that might be occurring in the eyes and lungs. However, in a model of dermal wound healing we have found that the rate of wound closure and the extent of wound angiogenesis were similar in wild-type and PECAM-1-null-mice or in mice treated with control IgG or anti-PECAM-1 antibody (data not shown).…”

“…19 However, subsequent studies have shown that the loss of PECAM-1 results in decreased neutrophil recruitment in response to interleukin-1 20,21 and in other inflammatory settings, 22,23 enhanced susceptibility to endotoxic shock, 24 increased endothelial sensitivity to apoptotic stress, 25 and impaired alveolarization. 26 To date, however, in vivo angiogenesis has been investigated in these animals in only a limited number of reports. 27,28 Studies were therefore performed in PECAM-1-null mice to more fully define the formation of vessels in several animal models, as well as the func-tional activity of ECs isolated from wild-type and PECAMnull mice.…”

Modulators of endothelial cell filopodia

“…11 In addition, post-natal lung development (a process dependent on angiogenesis) and the initial post-natal vascularization of the murine retina are impaired in PECAM-1-deficient mice. 11,44 Significantly, the vascular pattern and density in the eyes and lungs are similar in wild type and PECAM-1-null adult mice (unpublished observations), suggesting that the loss of PECAM-1 delays, but does not prevent the eventual development of the retinal or pulmonary vasculature. Together, these data implicate PECAM-1 in pathological angiogenesis, as well as in post-natal vascular developmental processes, such as those occurring in the eyes and lungs.…”