The systemic inflammatory response to infection is the leading cause of mortality in North American intensive care units. While much is known about inflammatory mediators, the relationships between microvascular heterogeneity, micro-regional inflammation, hypoxia-inducible gene expression and myocardial dysfunction are unknown. Male Sprague-Dawley rats were injected intraperitoneally with lipopolysaccharide (LPS) to test the hypothesis that sepsis induced local inflammation and increased microvascular heterogeneity are spatially and temporally related to hypoxia-inducible gene expression and decreased left ventricular contractility. Using a combination of 3-D microvascular imaging, tissue Po₂ and pressure-volume conductance measurements we found that five hours after LPS, minimum oxygen diffusion distances increased (p<0.05) while tissue oxygenation and contractility both decreased (p<0.05) in the left ventricle. Real-time RT-PCR analysis revealed that the hypoxia-inducible genes HIF-1, VEGF and GLUT1 were all upregulated (p<0.05) in the left ventricle. Tissue regions expressing ICAM-1, obtained using laser capture microdissection, had increased HIF-1 and GLUT1 (p<0.05) gene expression. VEGF gene expression was more diffuse. In LPS rats, GLUT1 gene expression correlated (p<0.05) with left ventricular contractility. In five hour hypoxic cardiomyocytes, we found strong transient HIF-1, weak VEGF, and greater prolonged GLUT1 gene expression. By comparison, the HIF-1, GLUT1 gene induction pattern was reversed in the left ventricle of LPS rats. Taken together, these results show that LPS induces hypoxia in the left ventricle associated with increased microvascular heterogeneity and decreased contractility. HIF-1 and GLUT1 gene induction are related to a heterogeneous ICAM-1 expression and may be cardioprotective during the onset of septic injury.