Perlecan in vascular disease

Atherosclerosis has become the most common cause of death in the world. The development of the disease involves accumulation of lipids in the inner layer of the vessel wall, the intima, and recruitment of inflammatory cells and smooth muscle cells (SMCs). A plaque that protrude into the lumen develops that may affect blood flow and ultimately rupture, thereby initiating thrombosis, vessel occlusion, and subsequent heart infarction and stroke. Surgical treatment of occlusive atherosclerotic lesions cause mechanical injury to the arterial wall, which triggers a healing response, intimal hyperplasia and may result in a renarrowing of arterial lumen, so-called restenosis.

SMC proliferation in the intima is part of a healing process in the intima that contributes stability to atherosclerotic plaques but is also the main feature of intimal hyperplasia. A well-controlled intimal hyperplasia in the healing response of SMCs is therefore desirable in order to control restenosis as well as in the preventing the devastating clinical consequences of plaque rupture.

Heparin, and heparan sulfate proteoglycans are established inhibitors of SMC proliferation based on studies using exogenous sources of heparin or heparan sulfate molecules. In addition, heparan sulfate is also expressed at low levels in atherosclerotic lesions. However, the role of heparan sulfate proteoglycans normally expressed in the vascular wall in the regulation of SMC proliferation as well as the identity of the proteoglycan down-regulated in human atherosclerosis were previously unknown.

Here, the role of the heparan sulfate proteoglycan perlecan, in the regulation of SMC proliferation and in human atherosclerosis was examined. First, perlecan was identified as the major heparan sulfate proteoglycan in the vessel wall in mice. In the formation of intimal hyperplasia in rats, an inverse correlation between the accumulation of perlecan and SMC proliferation was found. Transgenic mice expressing a heparan sulfate-deficient perlecan were shown to develop larger intimal lesions, due to increased SMC proliferation. In addition, perlecan was demonstrated to inhibit SMC adhesion to fibronectin in vitro.

We propose that perlecan may regulate the healing response of SMCs by binding and sequestering of heparin-binding growth factors and thereby limit interactions with receptors at the surface of SMCs. Perlecan may also influence SMC activation, migration and proliferation by modulating interactions with other matrix molecules such as fibronectin. With respect to atherogenesis, SMCs from mice and rats were shown to produce more heparan sulfate proteoglycans than human SMCs. In addition, the expression of perlecan was reduced in symptomatic carotid plaques from humans. The low production of heparan sulfate by human SMCs together with the lack of perlecan in human atherosclerosis may be key components in the atherogenicity of human arteries.

List of scientific papers

I. Lundmark K, Tran PK, Kinsella MG, Clowes AW, Wight TN, Hedin U (2001). Perlecan inhibits smooth muscle cell adhesion to fibronectin: role of heparan sulfate. J Cell Physiol. 188(1): 67-74.
https://pubmed.ncbi.nlm.nih.gov/11382923

II. Kinsella MG, Tran PK, Weiser-Evans MC, Reidy M, Majack RA, Wight TN (2003). Changes in perlecan expression during vascular injury: role in the inhibition of smooth muscle cell proliferation in the late lesion. Arterioscler Thromb Vasc Biol. 23(4): 608-14. Epub 2003 Feb 27
https://pubmed.ncbi.nlm.nih.gov/12615671

III. Tran PK, Tran-Lundmark K, Soininen R, Tryggvason K, Thyberg J, Hedin U (2004). Increased intimal hyperplasia and smooth muscle cell proliferation in transgenic mice with heparan sulfate-deficient perlecan. Circ Res. 94(4): 550-8. Epub 2004 Jan 22
https://pubmed.ncbi.nlm.nih.gov/14739157

IV. Tran PK, Tran-Lundmark K, Chan C, Ekstrand J, Braun K, Potter-Pergio S, Wight TN, Kinsella MK, Roy J, Hedin U (2005). Differences in production of heparan sulfate proteoglycans in human, mouse and rat vascular smooth muscle cells. [Manuscript]

V. Tran PK, Agardh HE, Tran-Lundmark K, Ekstrand J, Roy J, Henderson N, Babrielsen A, Hansson GK, Swedenborg J, Paulsson-Berne G, Hedin U (2005). Reduced perlecan expression and accumulation in human carotid atherosclerotic lesions. [Manuscript]