Tissue responses to ischemia binding of the transcription factor hypoxia-inducible factor-1 (HIF-1) to a hypoxia response element in the VEGF promoter (8). Endomyocardial biopsy specimens retrieved from patients undergoing coronary artery bypass surgery exhibit increased HIF-1 levels, associated with acute ischemia or early infarction (5). Increase in mRNA stability constitutes a second important control point for the hypoxic induction of VEGF in different cell lines (9). Stabilization of VEGF mRNA by hypoxia is thought to be mediated by the binding of sequence-specific RNA-binding proteins to sequences in both the 3′ and 5′ untranslated regions of VEGF mRNA. These interactions occur under the stress of hypoxia and extend the intrinsically short halflife of VEGF mRNA about fourfold (10). A third feature of VEGF that is critical for facilitating an efficient and sensitive response to hypoxia is the presence of an internal ribosome entry site that permits capindependent translation by ribosomal scanning of its mRNA (10). This may be particularly important because the 5′ untranslated region of the VEGF mRNA has several features that interfere with efficient ribosomal scanning, including its length, high G+ C content that permits secondary structure formation, and a short open reading frame bounded by in-frame initiation and termination codons. Importantly, Stein et al.(10) have shown that internal ribosome entry onto the VEGF mRNA is not diminished by the development of hypoxia. In vivo and in vitro studies document VEGF synthesis in skeletal (3) and cardiac myocytes (11), as well as in vascular endothelial cells (ECs) under conditions of hypoxia (3). Circulating T cells (12) and monocytes (13) provide another source of VEGF as they infiltrate into the necrotic/ischemic milieu. This property of infiltrating T cells was first described in the development of tumor neovasculature (14). The critical nature of this contribution has perhaps been best demonstrated in T cell–deficient nude mice that in response to hindlimb ischemia undergo necrotic autoamputation due to retarded angiogenesis (12, 15).