Role of FACIT Collagens in Hypertension

Project Details


(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.
Effective start/end date6/1/015/31/07


  • National Heart, Lung, and Blood Institute: $108,471.00
  • National Heart, Lung, and Blood Institute: $110,447.00
  • National Heart, Lung, and Blood Institute: $107,730.00
  • National Heart, Lung, and Blood Institute: $109,867.00
  • National Heart, Lung, and Blood Institute: $109,193.00


  • Pulmonary and Respiratory Medicine


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