Aims: Monocytes contribute to arteriogenesis by infiltration to sites of collateral growth and subsequent production and release of growth factors. Transforming growth factor β1 (TGF-β1) mediates monocyte motility and stimulates arteriogenesis. TGF-β1 signalling mechanisms mediating monocyte motility are unknown so far. Moreover, the influence of cardiovascular risk factor diabetes on TGF-β1-induced monocyte migration remains to be elucidated.
Methods and results: Stimulation of primary human monocytes with TGF-β1 endorsed phosphorylation of v-Akt murine thymoma viral oncogene analogues protein (AKT), p38, and extracellular signal-related kinase 1/2 (ERK1/2), besides the activation of the SMA/MAD homologues protein (SMAD) pathway. Inhibition of the TGF-βtype 1 receptor, alias activin receptor-like kinase 5 (ALK5), hindered monocyte chemotaxis towards TGF-β1 and TGF-β1-activated downstream signalling cascades. Individual genetic knock-downs for receptor-regulated SMAD2 and SMAD3 did not affect monocyte migration to TGF-β1. Inhibition of phosphoinositide 3 kinase (PI3K) activity, but not AKT, diminished both basal and TGF-β1-mediated monocyte motility. TGF-β1-induced monocyte chemotaxis did not rely on ERK1/2, but rather on p38. Remarkably, TGF-β1 was able to stimulate chemotaxis of diabetic monocytes.
Conclusion: The current study provides novel insights into the molecular mechanisms of TGF-β1-induced monocyte migration, requiring ALK5 kinase activity and signalling via PI3K and p38. TGF-β1-driven monocyte motogenicity is fully functional in diabetic conditions, which is in sharp contrast to the impaired chemotactic responses to certain other arteriogenic cytokines. Therefore, TGF-β1 may be a promising candidate for endogenously and exogenously stimulating collateral growth in diabetic patients.