How do endothelial cells facilitate repair?
Angiopoietin-1 tyrosine protein kinase receptor related Tie-2 signaling in endothelial cells plays a pivotal role in wound healing, vascular integrity and angiogenesis [25]. Individually, angiopoietin (ANG)-1 is essential for blood vessel growth and maturation, and ANG-2 acts in combination with vascular endothelial cell growth factor (VEGF) to initiate angiogenesis. In conditions like cancer, there is an upregulation and over-expression of ANG-2 [25].
ANG-1 is chemotactic for endothelial cells, but neither ANG-1 nor ANG-2 exert proliferative effects [26]. ANG-2 is a natural inhibitor of ANG-1. Endothelial cells express ANG-2 mRNA and protein, supporting the potential for autocrine activation of angiopoietin/Tie2. ANG-1 and Tie-2 are highly expressed in both arteries and veins [27] (Fig. 5).
Fig. 5 Schematic representation of the Ang2 effect on the vascular bed in normal conditions, inflammation, and cancer. Under normal physiological conditions, Ang2 levels are low, but are upregulated during inflammation or cancer. Ang2 acts on endothelial cells, increasing endothelial permeability and also on the pericytes, causing pericyte detachment from the basement membrane, further inducing vascular leakiness, immune or/and cancer cell trans-endothelial migration, and deterioration of the condition. Ang2 has been proposed as a marker for inflammatory conditions
(From Akwii RG. Cells 2019; 8:471. With permission)
The tyrosine kinase family of cell surface proteins plays an important role in vascular biology. In response to a variety of conditions/environment-specific signals, tyrosine kinases engage in proliferation, migration, differentiation and morphologic organization that aligns with surroundings tissues [28]. Tyrosine kinases are commonly distinguished from one-another according to structural and sequence characteristics e.g. vascular endothelial growth factors (VEGF-R1, VEGF-R2 and VEGF-R3). Each plays an essential role in maintaining vascular integrity [29].
The Tie [tyrosine kinase with immunoglobulin and epidermal growth factor (EGF) homology domains] receptor family represent a second sub-family of endothelial cell receptor tyrosine kinases identified as Tie-1 and Tie-2 [30]. Tie-1 and Tie-2 are vital to maintain growth and integrity of the vasculature, including endothelial cell-smooth muscle cell communication in vascular morphogenesis (see discussion above).
Infectious diseases affecting the lungs cause varying degrees of inflammation. Dysregulated inflammation is particularly deleterious and often associated with endothelial cell dysfunction. Trent et al. [31] reported dysregulated pulmonary inflammation and Tie-2-related endothelial dysfunction contributing to lung damage and mortality in a murine model of Orienta Tsutsugamushi infection. Tissue findings included a high level of Ang-2 proteins in pulmonary endothelial cells, a progressive loss of endothelial cell quiescent and junction proteins, and a substantial decrease in Tie-2 receptor at the transcriptional and functional levels. In-vitro infection of primary human endothelial cells demonstrated similar findings.
Tie-1 is upregulated by oscillating shear stress and differentially expressed in a dynamic pattern with disturbed flow [32]. Tie-1 deletion in mice causes abnormal extracellular matrix deposition and remodeling characterized by increased glycosaminoglycan and decreased collagen content. The findings suggest that abnormal blood flow is a stimulus for endothelial cell Tie1-mediated paracrine signaling.