Jonathan E. Shoag

Peripheral arterial disease (PAD) affects 5 million people in the US and is the primary cause of limb amputations. Exercise remains the single best intervention for PAD, in part thought to be mediated by increases in capillary density. How exercise triggers angiogenesis is not known. PPARgamma coactivator (PGC)-1alpha is a potent transcriptional co-activator that regulates oxidative metabolism in a variety of tissues. We show here that PGC-1alpha mediates exercise-induced angiogenesis. Voluntary exercise induced robust angiogenesis in mouse skeletal muscle. Mice lacking PGC-1alpha in skeletal muscle failed to increase capillary density in response to exercise. Exercise strongly induced expression of PGC-1alpha from an alternate promoter. The induction of PGC-1alpha depended on beta-adrenergic signaling. beta-adrenergic stimulation also induced a broad program of angiogenic factors, including vascular endothelial growth factor (VEGF). This induction required PGC-1alpha. The orphan nuclear receptor ERRalpha mediated the induction of VEGF by PGC-1alpha, and mice lacking ERRalpha also failed to increase vascular density after exercise. These data demonstrate that beta-adrenergic stimulation of a PGC-1alpha/ERRalpha/VEGF axis mediates exercise-induced angiogenesis in skeletal muscle.

tation. 1,3 Underreporting of jaw claudication may be a consequence of modern diets that require less mastication effort, particularly in the elderly population. The two cases reported here show that the chewing gum test (i.e., chewing gum at the rate of one chew per second) may be a simple and repeatable test for jaw claudication and allow for a better characterization of this symptom. In our patients, claudication of the jaw appeared after 2 to 3 minutes of chewing and resolved after prednisolone treatment.

In addition to their well-established role as regulators of allergic response, recent evidence supports a role for mast cells in influencing the outcome of physiologic and pathologic T cell responses. One mechanism by which mast cells (MCs) influence T cell function is indirectly through secretion of various cytokines. It remains unclear, however, whether MCs can directly activate T cells through Ag presentation, as the expression of MHC class II by MCs has been controversial. In this report, we demonstrate that in vitro stimulation of mouse MCs with LPS and IFN-gamma induces the expression of MHC class II and costimulatory molecules. Although freshly isolated peritoneal MCs do not express MHC class II, an in vivo inflammatory stimulus increases the number of MHC class II-positive MCs in situ. Expression of MHC class II granted MCs the ability to process and present Ags directly to T cells with preferential expansion of Ag-specific regulatory T cells over naive T cells. These data support the notion that, in the appropriate setting, MCs may regulate T cell responses through the direct presentation of Ag.