The role of tissue inhibitors of metalloproteinases in microvascular endothelial cell barrier dysfunction during sepsis

Figures & data

Figure 1 Common functions of tissue inhibitors of metalloproteinases (TIMPs) in microvascular endothelial cell (MVEC) barrier function.

Notes: In general, TIMPs promote MVEC barrier function and restrict inflammation, which occurs through a variety of metalloproteinase-dependent and metalloproteinase-independent mechanisms (blue bubbles). For example, TIMPs are involved in regulating the composition and structure of the extracellular matrix (ECM), largely through their ability to inhibit matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs), and ADAMs with thrombospondin repeats (ADAMTSs). Regulation of metalloproteinases also enables TIMPs to restrict the proinflammatory response by inhibiting shedding and/or activation of proinflammatory cytokines (eg, tumor necrosis factor α). Additionally, TIMPs appear to inhibit angiogenesis by binding to the VEGF receptor through metalloproteinase-independent mechanisms. While TIMPs appear to primarily function to stabilize the MVEC barrier, there is some limited, indirect evidence of TIMPs promoting barrier dysfunction (red bubbles). These mechanisms that have the potential to promote MVEC barrier dysfunction include promoting endothelial cell apoptosis, activation of latent MMPs, and the initiation of ECM accumulation leading to fibrosis.

Figure 2 Predicted metalloproteinase-dependent and metalloproteinase-independent functions of TIMP3 in MVECs.

Notes: (A) In the presence of TIMP3, MMPs and ADAM17/ tumor necrosis factor alpha converting enzyme (TACE) are inhibited. The structure and composition of the ECM as well as the MVEC intercellular junctions are maintained. Moreover, leukocyte adhesion and extravasation are limited. (B) In the absence of TIMP3, increased MMP activity leads to degradation of the ECM and proteins associated with intercellular junctions. Additionally, increased ADAM17 activity leads to increased release of TNFα, which propagates the proinflammatory response. Expression of leukocyte receptors, such as intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, is increased on the surface of MVECs. Moreover, shedding of these receptors by metalloproteinases is thought to promote leukocyte extravasation into the underlying tissue. Membrane-bound transforming growth factor α is also shed from the cell surface by ADAM17, resulting in binding to and activation of EGF receptors to promote cell proliferation, cell migration, and angiogenesis. (C) TIMP3 binds the VEGF receptor, inhibiting its downstream cascade by preventing interaction with and binding of its ligand, VEGF-A. TIMP3 also binds to and activates the angiotensin type II (AT2) receptor II. The combined effects of VEGF receptor inhibition and AT2 receptor II activation decrease cell proliferation and migration, inhibit angiogenesis, reduce vascular permeability, and inhibit leukocyte–EC interaction. (D) The absence of TIMP3 allows VEGF to bind to its receptor, activating the MAPK, protein kinase B, protein kinase C, and nitric oxide synthase pathways. This ultimately leads to increased expression of the early growth response protein 3 (Egr3) and phosphorylation of proteins associated with MVEC intercellular junctions. Moreover, the AT2 receptor II does not get activated due to the lack of TIMP3 binding. Overall, the combined effects of VEGF activation and AT2 receptor II inactivation result in increased cell proliferation and migration, increased angiogenesis, increased expression of cell surface adhesion molecules leading to leukocyte–EC interaction, and vascular permeability.
Abbreviations: TIMP3, tissue inhibitors of metalloproteinases; MVECs, microvascular endothelial cells; MMP, matrix metalloproteinases; ECM, extracellular matrix; ADAM, a disintegrin and metalloproteinase; TNFα, tumor necrosis factor alpha.