The major finding of this study is that PECAM-1 expression affects development of atherosclerosis differently at different lesion-prone sites of the vasculature. Specifically, PECAM-1 is pro-atherosclerotic in the inner curvature of the aortic arch, but atheroprotective in the aortic sinus, branching arteries, and descending aorta. The atheroprotective effect of PECAM-1 in the aortic sinus requires PECAM-1 expression only on endothelial cells, whereas PECAM-1 expression on both endothelial cells and bone marrow-derived cells is required for its atheroprotective effects in the descending aorta.
The pro-atherosclerotic effect of PECAM-1 in the inner curvature of the arch is consistent with its role as part of a mechanostimulatory complex on endothelial cells that activates NF-κB in response to low shear stress and induces expression of adhesion molecules that enable recruitment of inflammatory cells into the lesion9
. A mechanostimulatory function for PECAM-1 is supported by the findings in many9,31-33
, but not all34
, studies that PECAM-1 facilitates responses of cultured endothelial cells to osmotic and fluid shear stresses. Previous studies have established that PECAM-1 is rapidly phosphorylated on cytoplasmic tyrosine residues in cultured endothelial cells exposed to fluid shear or osmotic stress;31-36
however, whether PECAM-1 tyrosine phosphorylation is required for its mechanostimulatory function is not yet known.
The atheroprotective effect of PECAM-1 in the aortic sinus, branching arteries, and descending aorta indicates that PECAM-1 normally inhibits development of atherosclerosis in these regions of the vasculature. Our studies of bone marrow chimeric mice revealed that the cells on which PECAM-1 must be expressed to inhibit lesion development vary by vascular region. Specifically, in both the aortic sinus and descending aorta, the atheroprotective effect of PECAM-1 required its expression on endothelial cells; in the aortic sinus, PECAM-1 expression on endothelial cells alone was sufficient for its inhibitory function. Two functions of the endothelium that impact lesion development in atherosusceptible regions include maintenance of the vascular permeability barrier and insurance of nitric oxide (NO) bioavailability.2
PECAM-1 has been shown to support maintenance of vascular integrity in at least four different models of inflammation, including intradermal injection of histamine,11
and LPS-induced endotoxemia13,14
. PECAM-1 deficiency has also been shown to affect NO bioavailability, either as a consequence of decreased production of NO19
or increased production of reactive oxygen species.20
Thus, either increased vascular permeability or decreased NO bioavailability could contribute to the increased atherosclerosis observed in the aortic sinuses and descending aortas of mice with PECAM-1-deficient relative to PECAM-1-positive endothelium.
The inhibitory effect of PECAM-1 on lesion development in the aorta as a whole, in contrast, required its expression not only on endothelial cells but also on hematopoietic cells. The hematopoietic cells thought to play crucial roles in atherosclerotic lesion development include monocytes, T lymphocytes, and platelets.1,3
There is ample evidence that PECAM-1 inhibits platelet responsiveness30,37
and PECAM-1 is also capable of interfering with both macrophage-mediated phagocytosis of viable cells38,39,40
and T cell receptor-mediated signaling pathways.41
Indeed, loss of PECAM-1 from circulating T cells correlated with occurrence of atherothrombotic plaque complications in humans42
Furthermore, in vivo
administration of PECAM-1/IgG fusion proteins reduced lesion sizes in atherosusceptible mice coincident with blunted T cell activation, increased numbers of circulating regulatory T cells, and decreased infiltration of T cells into accumulating plaque.44
Collectively, these studies support the conclusion that interactions between PECAM-1 expressing endothelial cells and either platelets, monocytes or T cells may decrease atherosclerosis in aortas of PECAM-1-positive relative to PECAM-1-negative mice. Studies in which the pecam-1
gene is knocked out in specific types of hematopoietic cells are needed to determine the extent to which PECAM-1 expression by any one of these cell types normally interferes with development of atherosclerosis.
Finally, our findings indicate that PECAM-1 has both pro-atherosclerotic and atheroprotective effects on the vasculature; however, each of these opposing effects dominates in a different region of the vasculature. Thus, the inner curvature of the arch is more strongly influenced by the mechanostimulatory and therefore pro-atherosclerotic function of PECAM-1, whereas other atherosusceptible regions of the vasculature are more strongly influenced by its anti-inflammatory and therefore athero-protective effects. A possible explanation for the differential sensitivity of these regions to PECAM-1’s mechanosensory vs. anti-inflammatory roles is that PECAM-1 might influence the type and/or magnitude of hemodynamic shear stress to which different regions of the vasculature are exposed, which can be addressed by comparing the hemodynamic properties of PECAM-1+/+
Alternatively, PECAM-1 might contribute in different ways to the responses of cells in different regions of the vasculature, even if they are exposed to the same shear stresses. This possibility is consistent with the concept that site-specific responses to systemic factors modulate how atherosclerosis develops in different atherosusceptible regions.2
In either case, by demonstrating that PECAM-1 both promotes and impedes development of atherosclerotic lesions in site-specific ways, our findings provide a more complete understanding of the factors that interact in complex ways to control initiation and progression of atherosclerosis.