Background-Bartonella species are the only known bacterial pathogens causing vasculoproliferative disorders in humans (bacillary angiomatosis [BA]). Cellular and bacterial pathogenetic mechanisms underlying the induction of BA are largely unknown. Methods and Results-Activation of hypoxia-inducible factor-1 (HIF-1), the key transcription factor involved in angiogenesis, was detected in Bartonella henselae-infected host cells in vitro by immunofluorescence, Western blotting, electrophoretic mobility shift, and reporter gene assays and by immunohistochemistry in BA tissue lesions in vivo. Gene microarray analysis revealed that a B henselae infection resulted in the activation of genes typical for the cellular response to hypoxia. HIF-1 was essential for B henselae-induced expression of vascular endothelial growth factor as shown by inhibition with the use of HIF-1-specific short-interfering RNA. Moreover, infection with B henselae resulted in increased oxygen consumption, cellular hypoxia, and decreased ATP levels in host cells. Infection with a pilus-negative variant of B henselae did not lead to cellular hypoxia or activation of HIF-1 or vascular endothelial growth factor secretion, suggesting a crucial role of this bacterial surface protein in the angiogenic reprogramming of the host cells. Key Words: angiomatosis, bacillary Ⅲ Bartonella henselae Ⅲ angiogenesis Ⅲ HIF-1 protein Ⅲ hypoxia A ngiogenesis is a multistep process resulting in the formation of new blood vessels from preexisting vasculature. Newly formed vessels supply oxygen and nutrients to growing tumors and are necessary for tumor progression and metastasis. 1 Angiogenesis is also a component of various cardiovascular and inflammatory diseases. 2 Hypoxiainducible factor-1 (HIF-1) is a key transcription factor for the induction of angiogenic growth factors that adjust the vascular oxygen supply to tissue metabolic demands. 3,4 Of the many genes induced by HIF-1, vascular endothelial growth factor (VEGF) plays a critical role in triggering angiogenesis as the major hypoxia-inducible mitogen for endothelial cells. 5 Interestingly, human herpesvirus-8 (HHV-8) and several Bartonella species induce angiogenesis in humans. causes the vasculoproliferative disorder Kaposi's sarcoma, 6 which has a high frequency among immunocompromised patients, such as those infected with HIV. HHV-8 -infected cells express VEGF on HIF-1 activation, 7 and this mechanism was implicated in endothelial cell proliferation in the lesions. 8 Bartonella henselae and B quintana are the etiologic agents of bacillary angiomatosis (BA) and bacillary peliosis (BP), which are histologically characterized as lobulated proliferation of mainly capillary-sized vessels and predominantly affect HIV patients. 9 These slow-growing bacteria are facultative intracellular pathogens that, like HHV-8, also induce VEGF in host cells in vitro and in BA or BP lesions of patients. 10 Endothelial cells are one presumed habitat of Bartonella. 11 Dissecting the angioproliferative strategies used Received...