Background:In hypoxic cells, HIF-1 transactivates genes with roles in developmental, physiological, and disease processes. Results: HIF-1 activity in hypoxic fibroblasts promotes extracellular matrix (ECM) remodeling by inducing expression of the collagen hydroxylases P4HA1, P4HA2, and PLOD2. Conclusion: HIF-1 stimulates ECM fiber alignment, which influences cell morphology, adhesion, and directional migration. Significance: Hypoxia induces changes in ECM that have non-cell-autonomous effects on cell behavior.
Stiffening of conduit arteries is a risk factor for cardiovascular morbidity. Aortic wall stiffening increases pulsatile hemodynamic forces that are detrimental to the microcirculation in highly perfused organs such as the heart, brain and kidney. Arterial stiffness is associated with hypertension but presumed to be due to an adaptive response to increased hemodynamic load. In contrast, a recent clinical study found that stiffness precedes and may contribute to the development of hypertension, although the mechanisms contributing to hypertension are unknown. Here we report that in a diet-induced model of obesity, arterial stiffness, measured in vivo, develops within one month of the initiation of the diet and precedes the development of hypertension by five months. Diet-induced obese mice recapitulate the metabolic syndrome and are characterized by inflammation in visceral fat and aorta. Normalization of the metabolic state by weight loss returned arterial stiffness and blood pressure to normal. Our findings support the hypothesis that arterial stiffness is a cause, rather than a consequence of hypertension.
Metastasis is the leading cause of death among patients with breast cancer. Understanding the role of the extracellular matrix in the metastatic process may lead to the development of improved therapies for cancer patients. Intratumoral hypoxia is found in the majority of breast cancers and is associated with an increased risk of metastasis and patient mortality. Here we demonstrate that hypoxia-inducible factor 1 activates the transcription of genes encoding collagen prolyl hydroxylases that are critical for collagen deposition by breast cancer cells. We show that expression of collagen prolyl hydroxylases promotes cancer cell alignment along collagen fibers, resulting in enhanced invasion and metastasis to lymph nodes and lungs. Lastly, we establish the prognostic significance of collagen prolyl hydroxylase mRNA expression in human breast cancer biopsies, and demonstrate that ethyl 3,4-dihydroxybenzoate, a prolyl hydroxylase inhibitor, decreases tumor fibrosis and metastasis in a mouse model of breast cancer.
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