Laminar shear stress inhibits CXCR4 expression on endothelial cells: functional consequences for atherogenesis

Abstract

Laminar shear stress (LSS) represents a major athero-protective stimulus. However, the mechanisms for this effect are poorly characterized. As chemokine receptors modulate endothelial cell functions, we hypothesized that at least some LSS effects on endothelial cells (ECs) may be due to LSS-dependent changes in chemokine receptor expression and function. Exposure of Human umbilical vein endothelial cells (HUVECs) to 15 dynes/cm2/sec(-1) LSS strongly inhibited CXC chemokine receptor 4 (CXCR4) expression at the transcriptional level and impaired stromal-derived factor (SDF)-1/CXCL12-driven chemotaxis. On the contrary, low shear stress (SS; 4 dynes/cm2/sec(-1)) only marginally affected CXCR4 expression when compared with static control cells. Differently from CXCR4, the expression of SDF-1 mRNA was not affected by LSS treatment. CXCR4 overexpression induced a dose-dependent endothelial cell apoptosis that was enhanced by SDF-1 treatment and was caspase-dependent. CXCR4 overexpression inhibited the LSS-mediated antiapoptotic effect on ECs and was associated to impairment of LSS-induced ERK1/2 phosphorylation. These findings suggest that LSS-induced CXCR4 down-regulation may contribute to endothelial cell survival. Interestingly, the expression of the proatherogenic chemokines MCP-1 and IL-8 was induced by SDF-1 treatment and by CXCR4 overexpression in HUVECs. Further, the known LSS-induced inhibition of MCP-1 expression was impaired in CXCR4 overexpressing ECs. Finally, CXCR4 was abundantly expressed by human atherosclerotic plaque endothelium that is exposed to low/absent shear stress, while it was poorly expressed by minimally diseased carotid artery endothelium. In conclusion, LSS-dependent CXCR4 down-regulation may contribute to atheroprotection by favoring the integrity of the endothelial barrier and by inhibiting MCP-1 and IL-8 expression.

Circulating Bmp10 acts through endothelial Alk1 to mediate flow-dependent arterial quiescence

“…5D). Because expression of CXCR4 and EDN1 can be repressed or induced, respectively, by mechanical force in cultured endothelial cells (Wang et al, 1993;Melchionna et al, 2005), these results support the idea that Bmp10/Alk1/pSmad1/5/9 signaling may be crucial in transducing a mechanical signal into a biochemical response in arterial endothelial cells in vivo. In total, our results define a novel blood flow responsive signaling pathway -in which blood flow is required for alk1 expression as well as, via circulating Bmp10, Alk1 activity -that is crucial for flowdependent limitation of endothelial cell number in and therefore caliber of nascent arteries.…”

“…1B) . Given that mammalian orthologs CXCR4 and EDN1 are flow responsive in cultured human endothelial cells (Wang et al, 1993;Melchionna et al, 2005), these data suggest that Alk1 might act downstream of blood flow to control expression of these mechanoresponsive genes. Accordingly, if Alk1 signaling is sufficient downstream of blood flow, then restoration of alk1 in the absence of flow might be expected to rescue expression of cxcr4a and edn1.…”

“…Furthermore, either loss of blood flow or loss of alk1 results in increased expression of cxcr4a, which encodes a pro-angiogenic chemokine receptor, and decreased expression of endothelin 1 (edn1), which encodes a vasoconstrictive peptide . Both of these genes are flow responsive in cultured endothelial cells (Wang et al, 1993;Melchionna et al, 2005), suggesting that Alk1 might lie upstream of cxcr4a and edn1 in a mechanosensitive signaling pathway. In support of this hypothesis, blood flowmediated repression of cxcr4a correlates with diminished endothelial cell protrusive activity in nascent zebrafish arteries (Bussmann et al, 2011), and zebrafish alk1 mutants, which exhibit abnormally high levels of arterial cxcr4a, develop enlarged arteries containing supernumerary endothelial cells, suggestive of failed flow-induced suppression of endothelial cell migration or proliferation (Roman et al, 2002;Corti et al, 2011).…”

Activation of a TGF-β-Specific Multistep Gene Expression Program in Mature Macrophages Requires Glucocorticoid-Mediated Surface Expression of TGF-β Receptor II

“…Furthermore, ALOX5AP polymorphisms are associated with myocardial infarction and stroke (61). TREM1, an inflammation amplifier (62), and IL18R1, whose ligation leads to the activation of NF B, as well as CXCR4, a CXC chemokine receptor responsible for CXCL12-mediated chemotaxis, support inflammation and atherosclerosis (63)(64)(65). Taking into consideration the genes of the lipid metabolism and immune modulation groups, it remains an open question whether the TGF-␤-activated gene expression program in M2 macrophages would favor the development of atherosclerosis or contribute to the putative protective functions of TGF-␤ during atherosclerosis (66,67).…”

Vascular Rejuvenation Through the Stromal Cell-Derived Factor 1α/CXC Chemokine Receptor Type 4/Janus Kinase 2 Signalling Pathway

“…8 This discrepancy is likely attributable to the fact that EPCs are phenotypically and ontologically distinct from mature endothelial cells and rather share several characteristics with leukocytes. Indeed, although CXCR4 expression in resident endothelial cells mainly reflects activation and inflammation, the role of CXCR4 in circulating EPCs is to direct their homing to the injured endothelium through SDF-1␣ gradient sensing.…”