Vascular Wall Remodeling in Patients with Supravalvular Aortic Stenosis and Williams Beuren Syndrome

Abstract

Supravalvular aortic stenosis (SVAS) and Williams Beuren syndrome (WBS) can be considered as inherited diseases affecting the whole arterial tree and causing narrowing of the vessels. It has been reported that abnormal deposition of elastin in arterial walls of patients with SVAS and WBS leads to increased proliferation of arterial smooth muscle cells (SMC), which result in the formation of hyperplastic intimal lesions. In this work, we conducted morphological and morphometrical analysis with stenotic aortas from patients suffering from SVAS and WBS and from healthy control subjects and demonstrated that the amount of elastic fibers and the loss of integrity of vascular elastic fibers in the aortas reflect similar changes in the skin of patients with SVAS or WBS, as reported in our previous work conducted on skin in these pathological states. On the other hand, we conducted investigations on metalloproteinases (MMP2, MMP9, MMP7) and their specific tissue inhibitors TIMP1 and TIMP2 to verify their possible involvement in the etiopathogeny of SVAS and WBS. We particularly evidenced an altered MMP9/TIMP1 balance in favor of matrix degradation which could facilitate SMC migration and neointimal hyperplasia. Our findings suggest that elastinolytic enzymes secreted by arterial SMC, possibly including matrilysin 1, are critical for the development of arterial lesions in SVAS and WBS and contribute to perpetuate arterial stenosis in either SVAS or WBS.

Implication of Matrix Metalloproteinase 7 and the Noncanonical Wingless-Type Signaling Pathway in a Model of Kidney Allograft Tolerance Induced by the Administration of Anti-Donor Class II Antibodies

“…Furthermore, in the same model of tolerance induction to mismatched kidney grafts, anti-TGF-␤ mAb breaks the tolerance process (17). Finally, it is important to note that MMP7 has already been detected in smooth muscle cells in the medium and in the stenotic region in patients with supravalvular aortic stenosis and Williams Beuren syndrome and that remodeling of the stenotic part of the aorta has been shown to be an adaptive mechanism to preserve a correct function of the aorta (55).…”

Protease-Activated Receptor-1 Antagonist F 16618 Reduces Arterial Restenosis by Down-Regulation of Tumor Necrosis Factor α and Matrix Metalloproteinase 7 Expression, Migration, and Proliferation of Vascular Smooth Muscle Cells

“…MMP7 is known to be present in media and stenotic regions of vessels from patients with supravalvular aortic stenosis and Williams Beuren syndrome, but it is not expressed in normal artery (Dridi et al, 2005). In rat, the MMP7 mRNA was also poorly expressed in noninjured carotid arteries, but its expression increased 4-fold 24 h after balloon angioplasty (Fig.…”

Congenital heart defects in Williams syndrome

“…Nevertheless, both sporadic and familial cases are considered as a result of deletion of chromosome 7 (7q11.23) 7 . Deletion of the elastin gene on chromosome 7q11.23 leads to deficiency or abnormal deposition of elastin during cardiovascular development, leading to widespread cardiovascular abnormalities in WS 8 . The chromosomal region has been designated as "Williams-Beuren Syndrome chromosome region 1" (WBSCR1).…”

“…These data proved that ELN mutations caused SVAS 13 . Debates remain in terms of etiologies of vasculopathy in WS, on either by decrease of the synthesis of elastin 14 , or by abnormal deposition of elastin in the arterial walls 8 . Both were explained to be a pathway leading to thickening of the tunica media and smooth muscle cell hypertrophy 14 .…”