Life at the crossroads: the nuclear LINC complex and vascular mechanotransduction

Abstract

Vascular endothelial cells line the inner surface of all blood vessels, where they are exposed to polarized mechanical forces throughout their lifespan. Both basal substrate interactions and apical blood flow-induced shear stress regulate blood vessel development, remodeling, and maintenance of vascular homeostasis. Disruption of these interactions leads to dysfunction and vascular pathologies, although how forces are sensed and integrated to affect endothelial cell behaviors is incompletely understood. Recently the endothelial cell nucleus has emerged as a prominent force-transducing organelle that participates in vascular mechanotransduction, via communication to and from cell-cell and cell-matrix junctions. The LINC complex, composed of SUN and nesprin proteins, spans the nuclear membranes and connects the nuclear lamina, the nuclear envelope, and the cytoskeleton. Here we review LINC complex involvement in endothelial cell mechanotransduction, describe unique and overlapping functions of each LINC complex component, and consider emerging evidence that two major SUN proteins, SUN1 and SUN2, orchestrate a complex interplay that extends outward to cell-cell and cell-matrix junctions and inward to interactions within the nucleus and chromatin. We discuss these findings in relation to vascular pathologies such as Hutchinson-Gilford progeria syndrome, a premature aging disorder with cardiovascular impairment. More knowledge of LINC complex regulation and function will help to understand how the nucleus participates in endothelial cell force sensing and how dysfunction leads to cardiovascular disease.

Keywords: LINC complex; SUN protein; cytoskeleton; endothelial cell; lamin; mechanotransduction; nucleus; vascular disease.

FIGURE 1

The nuclear LINC (Linker of Nucleoskeleton and Cytoskeleton) complex. The LINC complex resides in the nuclear envelope and bridges the inner and outer nuclear membranes. Inner nuclear membrane proteins SUN1 and SUN2 bind both A-type and B-type lamins in the nucleoplasm. On the cytoplasmic side, SUN proteins form trimers and bind KASH proteins anchored in the outer nuclear membrane. KASH proteins (nesprins 1–4) extend into the cytoplasm and engage with the cytoskeleton. Nesprin-1 and 2 directly interact with actin filaments and, via motor proteins, with microtubules. Nesprin-4 also mediates microtubule binding by interacting with kinesin, while nesprin-3 indirectly binds to intermediate filaments via plectin. The lamin-binding proteins emerin and TMEM201 reside in the inner nuclear membrane and bind to the SUN proteins. In meiotic cells, the LINC complex formed by SUN/KASH-5/dynein is involved in chromosome movement by tethering the telomeres to microtubules. Created with BioRender.com.

FIGURE 2

Structure and alignment of SUN1 and SUN2. (A) Primary structure of SUN1 and SUN2. Lamin-binding domain (green), transmembrane domain (dark grey), cytoplasmic domain with coiled-coil domains (light grey), SUN domain (pink). Lamin domains bind lamins, SUN domains bind KASH proteins. Created with BioRender.com. (B) Amino-acid sequence alignment of SUN1 and SUN2. Identical amino acids (dark grey) and similar amino acids (light grey) show high degree of sequence conservation of the SUN domain (pink highlight) compared to the lamin-binding domain (green highlight).

FIGURE 3

The nuclear LINC complex in health and disease. Model showing proposed interactions among LINC complex components in Wild-Type (top panel) and Hutchinson-Gilford progeria syndrome (HGPS) (bottom panel) cells. Top: In Wild-Type, SUN/KASH protein complexes engage similarly with actin filaments and microtubules, resulting in balanced interactions between the nucleus and the cytoskeleton. Bottom: In HGPS, progerin expression leads to SUN1 and SUN2 accumulation at the nuclear envelope, causing an imbalance in LINC complexes with a preference for interaction with microtubules over actin filaments. SUN2 also clusters at the nuclear envelope/ER interface, sequestering Endoplasmic Reticulum (ER) chaperone proteins and inducing an ER stress response. Created with BioRender.com.