Smooth Muscle Cell – Extracellular Matrix Alterations in Genetic Vasculopathies

Abstract

Pathogenic variants in 11 genes predispose individuals to aneurysms and dissections of the thoracic aorta and in some cases, vascular complications throughout the arterial tree, termed heritable thoracic aortic disease (HTAD) (Renard M et al. JACC, 2018;72:605–615). These genes are involved in vascular smooth muscle cell (SMC) contraction and metabolism, extracellular matrix (ECM) integrity and transforming growth factor β (TGF β) signaling. A unifying hypothesis is that the mutated gene products contribute to altered mechano‐transduction leading to vasculopathy (Humphrey JD et al. Circ Res 2015;116:1448–1461; Pinard A, Jones GT, Milewicz DM. Circ Res 2019;124:588–606). The objective of this study was to employ light (LM) and electron (EM) microscopy to evaluate the thoracic aortic and other arterial tissue from individuals harboring pathogenic variants in the 11 established predisposition genes who underwent surgical aneurysm or dissection repair. These individuals (n) harbored pathogenic variants in the following genes: FBN1 (13), ACTA2 (6), TGFBR1 (7), TGFBR2 (3), TGFβ2 (3), SMAD3 (3), LOX (1), MYLK (1), PRKG1 (1), and COL3A1 (4); total 42. Arterial specimens were evaluated using LM consensus criteria (Halushka MK et al. Cardiovasc Pathol 2016;25:247–257). EM was performed on selected cases (Davis EC. Lab Invest 1993;68:89–99). By LM, specimens were graded (0 – 3+) for mucoid extracellular matrix accumulation (MEMA), elastic fiber fragmentation and/or loss (EFFL), SMC nuclear loss/laminar medial collapse (SMCNL/LMC), and overall medial degeneration (A 1–2, B 3–4, C 5–6, D 7–9); intimal lesions (0–3+) and medial dissection (+/−) also were noted. The 42 specimens included 17 with medial dissection and 25 non‐dissected aneurysms. By LM, cases showed a spectrum of extent and severity of medial degenerative changes: A mild 8 cases, B moderate 18 cases, C moderately severe 14 cases, and D severe 2 cases. By EM, COL3A1 specimens showed reduction of collagen fibrils and shape variations of residual collagen fibrils; elastin fiber connections to SMCs were intact. In contrast, specimens with mutations in the TGF β pathway exhibited multiple foci with deficiency of elastic fibers and loss of elastic fiber connections to SMC but had normal collagen ultrastructure. These results support the hypothesis that the pathogenesis of genetic vasculopathies involves structural defects in the interaction of ECM components and SMCs, including impairment of the elastin‐contractile unit directly or through loss of structural support provided by collagen.Support or Funding InformationLocal funds