Background— CD40 is a costimulatory molecule that acts as a central mediator of various immune responses, including those involved in the progression of atherosclerosis. Correspondent to its function, CD40 is present not only on many immune cells, such as antigen-presenting cells and T cells, but also on nonimmune cells, such as endothelial cells.

Methods and Results— Ex vivo analyses in mice revealed that CD40 is strongly expressed in distinct venous and capillary but not arterial endothelial cell populations. Therefore, we analyzed to what extent determinants of an arterial environment control CD40 expression in these cells. In vitro studies indicated that the presence of smooth muscle cells or exposure to cyclic stretch significantly downregulates CD40 expression in human endothelial cells. Interestingly, endothelial cells cocultured with smooth muscle cells upregulated CD40 expression in response to cyclic stretch through a transforming growth factor–β1/activin-receptor–like kinase-1 (Alk-1)–dependent mechanism. To corroborate that this mechanism also operates in arteries in vivo, we analyzed the expression of Alk-1 and CD40 at atherosclerosis-prone sites of the mouse aorta that also appear to be exposed to increased stretch. In wild-type mice, both Alk-1 and CD40 revealed a comparably heterogeneous expression pattern along the aortic arch that matched those sites in low-density lipoprotein–receptor–deficient mice where atherosclerotic lesions develop.

Conclusions— Cyclic stretch thus increases the abundance of CD40 in endothelial cells through transforming growth factor–β1/Alk-1 signaling. This mechanism in turn may be responsible for the heterogeneous expression of CD40 at arterial bifurcations or curvatures and would support a site-specific proinflammatory response that is typical for the early phase of atherosclerosis.