Basement membrane heparan sulfate in atherogenesis and intimal hyperplasia

Cardiovascular disease due to atherosclerosis has become the leading cause of mortality in the world. Atherosclerosis is a progressive disease characterized by the accumulation of lipids, inflammatory cells, smooth muscle cells (SMCs) and extracellular matrix in the wall of large and medium-sized arteries. Surgical treatment of atherosclerosis cause mechanical injury to the vessel wall, which in many cases leads to restenosis and graft stenosis and recurrence of symptoms.

Intimal SMC proliferation contributes to the stability of atherosclerotic plaques but it is also the main feature of intimal hyperplasia, which contributes to restenosis. It is therefore important to understand the mechanisms that control SMC growth in order to achieve a balanced healing response following interventions. This can be illustrated by the use of stents that elute anti-proliferative drugs, which has recently been associated with a higher risk of late stent thrombosis due to impaired intimal healing.

Here, the role of basement membrane heparan sulfate (HS) in intimal hyperplasia and atherogenesis was investigated. Exogenously added heparin and HS are known inhibitors of SMC proliferation. However, the role of perlecan, which is the major arterial HS proteoglycan, in vascular disease was previously largely unknown. In vitro, the HS chains of perlecan lead to altered interactions between SMCs and fibronectin, possibly due to conformational changes in the fibronectin molecule. Such interactions may influence SMC function in atherogenesis and vascular repair processes. The use of transgenic mice expressing an HS-deficient perlecan showed increased SMC proliferation in vitro and increased intimal hyperplasia in vivo, confirming a growth inhibitory role for perlecan HS. A possible mechanism is decreased bioavailability of heparin-binding growth factors like FGF-2 at the cell surface due to sequestering in the basement membrane.

In order to study the role of HS in atherogenesis the HS-deficient mice were cross-bred with apolipoprotein E null mice, which develop atherosclerosis. The results from that study indicate that the perlecan HS chains are pro-atherogenic in mice through increased lipoprotein retention, and the ability of HS to inhibit SMC growth may contribute to lesion instability. However, when binding and retention are not limiting factors, the perlecan HS chains may be anti-atherogenic by reducing endothelial permeability to lipoproteins. To investigate how perlecan can be pharmacologically regulated we explored the effect of all-trans-retinoic acid (AtRA) on perlecan expression in SMCs. AtRA was shown to up-regulate perlecan and the inhibition of SMC proliferation by AtRA is secondary to an increased expression of perlecan and dependent upon its HS chains.

In summary, the role of basement membrane HS in vascular disease is complex. It may enhance lipoprotein retention, but also decrease endothelial permeability to lipoproteins. In addition, it can reduce restenosis, but maybe also cause plaque instability. This makes perlecan a difficult but very intriguing target for pharmacological interventions.

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. 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

III. Tran-Lundmark K, Tran PK, Paulsson-Berne G, Fridén V, Soininen R, Tryggvason K, Wight TN, Kinsella MG, Borén J, Hedin U (2008). Heparan sulfate in perlecan promotes mouse atherosclerosis: roles in lipid permeability, lipid retention and smooth muscle cell proliferation. Circulation Research. [Submitted]

IV. Tran-Lundmark K, Tran PK, Rauch B, Ekstrand J, Wight TN, Hedin U, Kinsella MG (2008). Heparan sulfate chains on perlecan are required for the inhibition of arterial smooth muscle cell proliferation by all-trans-retinoic acid. [Submitted]