Organotypic heterogeneity in microvascular endothelial cell responses in sepsis-a molecular treasure trove and pharmacological Gordian knot

Abstract

In the last decades, it has become evident that endothelial cells (ECs) in the microvasculature play an important role in the pathophysiology of sepsis-associated multiple organ dysfunction syndrome (MODS). Studies on how ECs orchestrate leukocyte recruitment, control microvascular integrity and permeability, and regulate the haemostatic balance have provided a wealth of knowledge and potential molecular targets that could be considered for pharmacological intervention in sepsis. Yet, this information has not been translated into effective treatments. As MODS affects specific vascular beds, (organotypic) endothelial heterogeneity may be an important contributing factor to this lack of success. On the other hand, given the involvement of ECs in sepsis, this heterogeneity could also be leveraged for therapeutic gain to target specific sites of the vasculature given its full accessibility to drugs. In this review, we describe current knowledge that defines heterogeneity of organ-specific microvascular ECs at the molecular level and elaborate on studies that have reported EC responses across organ systems in sepsis patients and animal models of sepsis. We discuss hypothesis-driven, single-molecule studies that have formed the basis of our understanding of endothelial cell engagement in sepsis pathophysiology, and include recent studies employing high-throughput technologies. The latter deliver comprehensive data sets to describe molecular signatures for organotypic ECs that could lead to new hypotheses and form the foundation for rational pharmacological intervention and biomarker panel development. Particularly results from single cell RNA sequencing and spatial transcriptomics studies are eagerly awaited as they are expected to unveil the full spatiotemporal signature of EC responses to sepsis. With increasing awareness of the existence of distinct sepsis subphenotypes, and the need to develop new drug regimen and companion diagnostics, a better understanding of the molecular pathways exploited by ECs in sepsis pathophysiology will be a cornerstone to halt the detrimental processes that lead to MODS.

Keywords: -omics; animal models; biomarkers; endothelial cell heterogeneity; human studies; multiple organ dysfunction syndrome; pharmacology; sepsis.

Figure 1

Schematic presentation of progression of organ loss in sepsis in response to an invading pathogen. Initially, the host senses the infectious microorganism that results in a local defence response to eliminate the pathogen and restore tissue homeostasis. (A dysregulated host response can lead to systemic inflammation and organ dysfunction, exemplified here for the lung, eventually leading to failure of multiple organs and death. Examples of specific organ failure as seen in the clinic are listed. The order and kinetics of organ systems affected are arbitrarily chosen and do not occur in a sequential fashion per se. ARDS, acute respiratory distress syndrome; AKI, acute kidney injury; BUN, blood urea nitrogen; ALT/AST, alanine transaminase/aspartate transaminase; CRP/SAA, C-reactive protein/serum amyloid A.

Figure 2

Schematic presentation of the gross architecture of blood vessels in an adult vertebrate. The cellular composition of blood vessels changes along the vascular tree where arterioles transport the blood from arteries into the tissue capillaries, and postcapillary venules transport it back to the bigger veins. Vascular permeability and leukocyte recruitment is predominantly regulated at the level of the capillaries and postcapillary venules, which show organ-specific structural differences based on inter-endothelial connections with continuous capillaries allowing the most controlled passage of blood and soluble components in the blood, and discontinuous capillaries allowing free passage. Although vessels are often categorised based on diameter, scRNA-seq studies have shown that there is a continuum of transcriptional states in ECs across the different branches of the vascular tree.

Figure 3

Schematic showing molecular systems important in endothelial (patho)physiology. Activation of receptors provides the microvascular ECs a pro-inflammatory, permeable, and coagulant status. The receptors and their ligands include examples discussed in the text, yet are not all encompassing. Of note, although TLR4 is traditionally known as a transmembrane receptor in myeloid cells, previous studies have demonstrated its intracellular location and function in ECs (87, 88). The reader is referred to Luxen et al. (90) for more detailed information on the signal transduction cascades that are activated by the receptors shown. APC, activated protein C; angpt, angiopoietin; EPCR, endothelial protein C receptor; LPS, lipopolysaccharide; PAR1, protease-activated receptor 1; PC, protein C; S1P(R), spingosine-1-phosphate (receptor); T, thrombin; Tie, tunica intima endothelial kinase; TLR, Toll-like receptor; TM, thrombomodulin; TNF(R), tumour necrosis factor (receptor); VEGF(R2), vascular endothelial growth factor (receptor 2).