Role of FACIT Collagens in Hypertension

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DESCRIPTION (Applicant's abstract) Pulmonary hypertension may be either a primary event, or secondary to other injury. In either case it is an important clinical problem in which the walls of injured blood vessels rapidly thicken. Part of this rapid thickening is caused by the de novo synthesis of the extracellular matrix components that help define the medical and adventitial layers of the blood vessels. This thickening in turn can result in decreased lumen diameter, increasing resistance to blood flow and ultimately raising arterial pressure. In animals, the damage is reversible if the disease has not progressed and if the underlying cause is removed. This hypertension regression has been well documented in animal models, but little is known about the normal mechanisms regarding this remodeling of the vessels. In particular, the rat model of hypoxic pulmonary hypertension is frequently used as it has in common many of the features of the human disease. Collagens play a major role in the development of mature, functional tissues. The extracellular matrix of connective tissue is composed, in part, of heterotypic collagen fibrils. Ultrastructurally, various connective tissue have different collagen fibrillar arrangements and alignments, however, despite the appearance of the fibrils, the types of collagens found in the fibrils are frequently the same, their spatial arrangements determined by molecules associated with the surfaces of fibrils or fibril bundles that establish and/or stabilize the various spatial arrangements. Such molecules would be expected to contain at least two domains: One domain that anchors the molecule to the surface of the fibril and a second domain to assist in various interactions with other fibrils or other matrix components. Proteins with such characteristics include collagens IX, XII, and XIV, which are classified as Fibril Associated Collagens with Interrupted Triple-helices (FACITs). Of this class of molecules, collagens XII and XIV are found in a variety of tissues that contain type I collagen and sit on the surface of the collagen I fibrils in an unknown capacity. We hypothesize that types XII and XIV collagen are recruited to temporarily stabilize fibril interactions under conditions of stress, such as hypoxia. This fibril stabilization would allow the tissue architecture to withstand the forces generated by a rapid increase in fibrillar collagen content and rapid cell proliferation. We also hypothesize that the types XII and XIV collagen are responsible for the reversibility of the vessel wall changes. These molecules are easily removed from fibril surfaces, allowing more permanent stabilizers to take their places (such as fibril fusion or lysly crosslinking), which are fibril adaptions that make the vessel changes permanent. We propose to examine the role of these collagens in the hypertensive rat model using a variety of biochemical and molecular biological techniques.