Table 2 The primary constituents of the ECM

Collagen

1. Constituting approximately 30% of the total protein mass in mammals, collagen serves as the primary constituent of the ECM [41]

2. It plays a crucial role in providing structural support, maintaining tissue shape, and preserving mechanical properties [41, 42]

3. Collagen interacts with cells through multiple receptor families, regulating their growth, mobility, and specialized development [41,42,43]

4. Accumulation and cross-linking of collagen can lead to ECM stiffening, potentially disrupting tissue architecture and promoting the progression of malignancies [20, 44]

5. The increase in collagen cross-linking is facilitated by enzymes such as lysyl oxidase (LOX) and LOX-like enzymes and stimulates signal transduction through cell surface receptors bound to collagen, including integrins [15]

6. Collagen degradation primarily relies on the action of matrix metalloproteinases (MMPs). Different types of MMPs can degrade fibrous collagen types I, II, and III [12]

Elastin

1. Elastin is primarily composed of elastic fibers in the matrix tissue and serves as the primary contributor to arterial fiber elasticity [47, 48]

2. Elastic fibers provide elasticity in the structure of blood vessel walls, the heart, lungs, skin, ligaments, tendons, and other tissues [49]

3. Elastin not only functions mechanically in blood vessels but also transmits mechanical signals, inhibits SMC proliferation, and regulates cell migration [37]

FN

1. FN is a glycoprotein composed of two nearly identical polypeptide chains connected by a pair of disulfide bonds, forming a dimer [48]

2. It has an approximate molecular weight of 250 kDa and consists of repetitive units of FNI, FNII, and FNIII [48]

3. The FN molecule contains multiple domains capable of binding to various ECM proteins, growth factors, and small molecules [52]

4. FN can simultaneously interact with cell surface receptors, integrins, collagen, proteoglycans (PGs), and other ECM proteins, thereby anchoring cells to the ECM and facilitating signal transduction between the cell and the ECM [52]

5. The presence of FN may play a pivotal role in the transition of static contractile smooth muscle cells to migratory, synthetic, and proliferative phenotypes [55]

Laminin

1. Laminin is a glycoprotein composed of three distinct subunits: α, β, and γ, which come together to form a larger composite structure [57, 58]

2. The short arms of each laminin subtype play a crucial role in the polymerization of laminin and its interactions with the cell surface [57, 58]

3. The distinct domains of each subtype can bind to different ECM and cell surface structures [57, 58]

4. The short arms of laminin interact with other extracellular matrix proteins, such as collagen, while the long arms can bind to integrins, facilitating dynamic connections between the extracellular and intracellular environments through bidirectional signaling and coordinating extracellular matrix, cytoskeletal, and signaling molecules within the cell [12, 59]

GAGs

1. GAGs are large polysaccharides composed of repeating disaccharide units, encompassing amino sugars and uronic acid. They can be categorized into two primary types: sulphated GAGs and non-sulphated GAGs [49, 61]

2. GAGs possess strong water-retention capabilities, leading to gel formation and imparting viscosity to tissues [49, 61]

3. The formation of PGs occurs through the covalent attachment of GAG chains to a core protein [49, 61]

4. Heparin, derived from sulphated GAGs, not only exhibits anticoagulant properties but also inhibits the proliferation of vascular smooth muscle cells (SMCs) [62, 63]

PGs

1. PGs have complex three-dimensional structures, consisting of a core protein covalently linked to one or more GAG chains at specific locations [12, 65,66,67]

2. Various pathological factors can lead to the abundant production of PGs in blood vessels [68]

3. Lumican is a leucine-rich member of the small PG family that can regulate cell proliferation and potentially act as an endogenous regulator of the TGF-β signaling pathway [69]

4. Sulphated GAGs, such as the low-density HS-PG, have the capability to bind growth factors like FGF2 and regulate cell proliferation [70]

5. Endocan is a soluble PG composed of DS. It is primarily synthesized and released by vascular endothelial cells and possesses pro-inflammatory properties [71, 72]

HA

1. HA is a unique glycosaminoglycan (GAG) that forms non-covalent bonds with ECM proteins [49, 74]

2. HA has the capacity to absorb up to 1000 times its weight in water, contributing to tissue viscosity and elasticity [49, 74]

3. HA plays a role in regulating factors related to angiogenesis, endothelial function, and vascular tension [75, 76, 78, 79, 126]

Integrins

1. Integrins are composed of non-covalently linked α and β subunits, forming heterodimeric transmembrane proteins [12, 41, 80,81,82]

2. Integrins can combine to produce a minimum of 24 different heterodimers, each exhibiting distinctive tissue distribution and function [12, 41]

3. Integrins can transmit information from the ECM to the cell interior by coordinating with other intracellular signaling molecules, such as Focal Adhesion Kinase ( FAK) and Src tyrosine kinases [12, 41, 80,81,82]

4. When blood vessels undergo remodelling leading to increased ECM stiffness, mechanical signals activate key signaling pathways, including the Hippo pathway, YAP, and TAZ, through integrins [85]

5. The interaction between integrin α5β1 and the ECM may also lead to endothelial cell inflammation and the development of atherosclerosis by promoting the expression of NF-κB and other inflammatory factors [88,89,90]

MMPs

1. MMPs are predominantly distributed within the ECM and are also present in cell membranes, thus playing a crucial role in altering tissue microstructure and participating in various biological and physiological processes [94]

2. The expression of MMPs is regulated by various factors, including inflammatory cytokines such as TNFα, IL-1β, oxidative stress, and mechanical forces such as stretching and shear stress [95,96,97,98]

3. MMPs can degrade most ECM components [16]

4. The Hippo/YAP pathway and the FPR2/ERK1/2 pathway may be involved in the activation of MMP-9 and early brain injury after SAH [104, 105]

TIMPs

1. The structure of TIMPs comprises two adjoining domains: the N-terminal domain, commonly referred to as the “inhibitory domain,” and the C-terminal domain [110]

2. Except for TIMP-3, all TIMPs inhibit MMPs through reversible blocking mechanisms [108, 110]

3. In addition to MMPs, TIMPs can also inhibit members of the disintegrin and metalloproteinase family and disintegrin and metalloproteinase with thrombospondin motifs [108, 109]