The cellular origin of laminin determines its role in blood pressure regulation

Abstract

Laminin of different cellular source has distinct functions. In addition to vascular smooth muscle cells (SMCs), aorta also contains a small population of nestin+ cells, whose function remains unknown. This study investigates the role of SMC- and nestin+ cell-derived laminin in blood pressure (BP) regulation and SMC contractibility. Using mice with laminin deficiency in SMCs (SKO) or nestin+ cells (NKO), we examined laminin-dependent changes in baseline BP. Contractile protein expression was reduced in SKO but not NKO mice, consistent with their respectively low and normal baseline BP measurements. At the ultrastructural level, SKO SMCs maintained the contractile phenotype with reduced elasticity, whereas NKO SMCs switched to the synthetic phenotype and showed degeneration. Additionally, angiotensin II (Ang II) significantly increased BP in SKO but not NKO mice. It also enhanced contractile proteins to the same levels and induced SMC degeneration in both knockout mice. These data suggest that SMC laminin regulates BP via modulating contractile protein expression, whereas nestin+ cell-derived laminin contributes to SMC phenotypic switch.

The role of pericytic laminin in blood brain barrier integrity maintenance

“…The specificity of the Transgelin promoter has been validated in a variety of studies313233. The SKO mice are born at expected Mendelian ratio with no gross abnormality, although they have a lower blood pressure12. Immunohistochemical analysis revealed negligible levels of IgG and hemoglobin in SKO brains (Fig.…”

“…3c) in our lineage-tracing experiment. To further determine whether the CNS phenotype is due to loss of laminin in pericytes or VSMCs, we also generated a VSMC-specific conditional knockout line (laminin γ1 flox/flox :Transgelin/SM22α-Cre + , termed SKO hereafter) by crossing the laminin γ1 flox/flox mice with the Transgelin/SM22α-Cre + line12. The specificity of the Transgelin promoter has been validated in a variety of studies313233.…”

“…It has a variety of biological functions, including cell adhesion, cell differentiation, and BM assembly, which explains its important roles in embryonic development, organogenesis, and vascular integrity891011. Recently, we have shown that laminin’s functions are dependent on its cellular origins since different cell types synthesize distinct laminin isoforms12. For example, brain endothelial cells make laminin-α4β1γ1 (−411) and -α5β1γ1 (−511)131415, whereas astrocytes generate laminin-α1β1γ1 (−111) and -α2β1γ1 (−211)1516.…”

Laminins and their receptors in the CNS

“…It should be noted that the PDGFRβ promoter is not pericyte-specific: it targets mural cells (both pericytes and SMCs) (Foo et al, 2006;Gautam et al, 2016). To distinguish pericyte-and SMC-derived laminins, we generated a SMC-specific conditional knockout line (termed SKO hereafter) by crossing laminin-γ 1 flox/flox mice with the Transgelin-Cre line (Yao, Norris & Strickland, 2015). Driven by the Transgelin promoter, Cre is specifically activated in SMCs but not pericytes (Holtwick et al, 2002;Miano et al, 2004;Lepore et al, 2005).…”

Atg7 Silencing Inhibits Laminin‐5 Expression to Suppress Tube Formation by Brain Endothelial Cells

“…The laminins are a family of 16 heterotrimeric glycoproteins that are located in the ECM (Kidd et al, 2005;Yao et al, 2015). The functions of laminin-8 and laminin-10 have been well investigated in angiogenesis (Marchand et al, 2018).…”