Time Course of Endothelial Cell Proliferation and Microvascular Remodeling in Chronic Inflammation

Abstract

Angiogenesis and vascular remodeling are features of many chronic inflammatory diseases. When diseases evolve slowly, the accompanying changes in the microvasculature would seem to be similarly gradual. Here we report that the rate of endothelial cell proliferation and the size of blood vessels increases rapidly after the onset of an infection that leads to chronic inflammatory airway disease. In C3H mice inoculated with Mycoplasma pulmonis, the tracheal microvasculature, made visible by perfusion of Lycopersicon esculentum lectin, rapidly enlarged from 4 to 7 days after infection and then plateaued. Diameters of arterioles, capillaries, and venules increased on average 148, 214, and 74%, respectively. Endothelial cell proliferation, measured by bromodeoxyuridine (BrdU) labeling, peaked at 5 days (18 times the pathogen-free value), declined sharply until day 9, but remained at ϳ3 times the pathogen-free value for at least 28 days. Remodeled capillaries and venules were sites of focal plasma leakage and extensive leukocyte adherence. Most systemic manifestations of the infection occurred well after the peak of endothelial proliferation, and the humoral immune response to M. pulmonis was among the latest, increasing after 14 days. These data show that endothelial cell proliferation and microvascular remodeling occur at an early stage of chronic airway disease and suggest that the vascular changes precede widespread tissue remodeling. Angiogenesis and vascular remodeling are important elements of the pathophysiology of cancer and chronic inflammatory diseases and may be essential for the persistence of these conditions. 1 The vasculature provides metabolic support for the diseased tissues and serves as the gatekeeper for incoming inflammatory cells and outgoing tumor cells that form metastases. The recognition that newly formed and remodeled vessels are different from those normally present led to the identification of probes to target diseased vessels selectively 2,3 and to the use of angiogenesis inhibitors in the treatment of cancer and chronic inflammation. 1,4 The properties and functional implications of angiogenic blood vessels have been examined in many animal models of cancer, 5-8 but less is known about the vascular changes in chronic inflammation. One might expect the microvasculature to change gradually as protracted inflammatory diseases evolve, or it could change rapidly at the beginning and drive other aspects of the disease. Yet the time course of changes in the vasculature in chronic inflammation has not been addressed systematically, in part because of limited suitable animal models.One animal model that has been useful for studying angiogenesis and vascular remodeling in chronic inflammation is the respiratory tract infection caused by Mycoplasma pulmonis in mice and rats. This infection causes severe, lifelong changes in the microvasculature of the airway mucosa, 9 -11 along with extensive tissue remodeling, leukocyte influx, epithelial and gland hyperplasia, and fibrosis in the airways and, in ...

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