Evolutionary Protection of Krüppel-Like Factors 2 and 4 in the Development of the Mature Hemovascular System

Abstract

A properly functioning hemovascular system, consisting of circulating innate immune cells and endothelial cells (ECs), is essential in the distribution of nutrients to distant tissues while ensuring protection from invading pathogens. Professional phagocytes (e.g., macrophages) and ECs have co-evolved in vertebrates to adapt to increased physiological demands. Intercellular interactions between components of the hemovascular system facilitate numerous functions in physiology and disease in part through the utilization of shared signaling pathways and factors. Krüppel-like factors (KLFs) 2 and 4 are two such transcription factors with critical roles in both cellular compartments. Decreased expression of either factor in myeloid or endothelial cells increases susceptibility to a multitude of inflammatory diseases, underscoring the essential role for their expression in maintaining cellular quiescence. Given the close evolutionary relationship between macrophages and ECs, along with their shared utilization of KLF2 and 4, we hypothesize that KLF genes evolved in such a way that protected their expression in myeloid and endothelial cells. Within this Perspective, we review the roles of KLF2 and 4 in the hemovascular system and explore evolutionary trends in their nucleotide composition that suggest a coordinated protection that corresponds with the development of mature myeloid and endothelial systems.

Participation of Krüppel-like Factors in Atherogenesis

“…The KLF4 factor has a similar structure and function to KLF2, and of all members of the KLF family, it is the most similar to KLF2 [ 39 ]. Expression of KLF4 is similar in tissue specificity to KLF2 and is characteristic of tissues such as vascular endothelium, lymphoid cells, skin epithelial cells, intestine, kidney, and lung [ 30 , 40 , 41 ].…”

“…Expression of KLF4 is similar in tissue specificity to KLF2 and is characteristic of tissues such as vascular endothelium, lymphoid cells, skin epithelial cells, intestine, kidney, and lung [ 30 , 40 , 41 ]. Like KLF2, KLF4 is activated by shear stress in endothelial cells [ 39 , 42 , 43 ]. These transcription factors are more highly expressed in straight vessel segments and decreased at branch sites, which are areas of the vascular network more susceptible to atherosclerosis [ 44 , 45 , 46 , 47 ].…”

Immune Function of Endothelial Cells: Evolutionary Aspects, Molecular Biology and Role in Atherogenesis

“…In addition, shear stress activates several transcription factors, such as Krüppel-like Factor 2 (KLF2) and KLF4, which, in turn, alter the expression of several genes and are essential for maintaining endothelial integrity and quiescence [ 73 , 74 , 75 , 76 ]. Laminar blood flow was found to induce KLF2 and KLF4 expression in the vascular endothelium, whereas KLF2 and KLF4 expression is reduced in areas of impaired blood flow as well as in areas prone to atherosclerosis [ 77 , 78 , 79 , 80 ].…”

“…Interestingly, KLF2 and KLF4 show functional overlap in myeloid and endothelial cells, showing a similar evolutionary trajectory and relationship [ 75 ]. KLF4 in myeloid cells has been shown to be an important regulator of the early proinflammatory immune response [ 84 ].…”

“…Interestingly, in humans and mice, consumption of fatty foods reduces levels of myeloid KLF2, which is a nodal regulator of central and peripheral metabolic inflammation [ 85 ]. In turn, KLF4, through transcriptional interactions with STAT6, modulates stimulate alternative (M2) macrophage polarization [ 75 , 86 , 87 ]. It is also suggested that the KLF4/eNOS signaling pathway may be involved in the EndMT process [ 88 ].…”