Endothelial pyruvate kinase M2 maintains vascular integrity

Abstract

The M2 isoform of pyruvate kinase (PKM2) is highly expressed in most cancer cells, and has been studied extensively as a driver of oncogenic metabolism. In contrast, the role of PKM2 in nontransformed cells is little studied, and nearly nothing is known of its role, if any, in quiescent cells. We show here that endothelial cells express PKM2 almost exclusively over PKM1. In proliferating endothelial cells, PKM2 is required to suppress p53 and maintain cell cycle progression. In sharp contrast, PKM2 has a strikingly different role in quiescent endothelial cells, where inhibition of PKM2 leads to degeneration of tight junctions and barrier function. Mechanistically, PKM2 regulates barrier function independently of its canonical activity as a pyruvate kinase. Instead, PKM2 suppresses NF-kB and its downstream target, the vascular permeability factor angiopoietin 2. As a consequence, loss of endothelial cell PKM2 in vivo predisposes mice to VEGF-induced vascular leak, and to severe bacteremia and death in response to sepsis. Together, these data demonstrate new roles of PKM2 in quiescent cells, and highlight the need for caution in developing cancer therapies that target PKM2.

Sirtuin 3 governs autophagy‐dependent glycolysis during Angiotensin II‐induced endothelial‐to‐mesenchymal transition

“…To examine the impact of the oligomeric status of PKM2 on lactate production, we induced PKM2 tetrameric assembly using the small molecule TEPP-46, a selective PKM2 tetramer activator. 39 In the present study, TEPP-46 not only significantly suppressed the production of lactate but also led to a reduction in EndoMT in vitro and in vivo. A recent study also reported that HK2, a rate-limiting glycolytic enzyme, regulates glycolytic metabolism by autophagic degradation in liver cancer.…”

“…Because PKM2 exists almost exclusively as a dimer in MAECs, we measured the lactate concentration under various conditions, which is an indirect reflection of PKM2 dimer enzymatic activities. To examine the impact of the oligomeric status of PKM2 on lactate production, we induced PKM2 tetrameric assembly using the small molecule TEPP‐46, a selective PKM2 tetramer activator 39 . In the present study, TEPP‐46 not only significantly suppressed the production of lactate but also led to a reduction in EndoMT in vitro and in vivo.…”

Nitric oxide maintains endothelial redox homeostasis through PKM 2 inhibition

“…It has been widely studied in cancer, as its expression is responsible for the Warburg effect (Christofk et al , ). While in numerous cell types both the PKM1 and PKM2 isoforms are expressed, only PKM2 is abundantly expressed in endothelial cells, where it contributes to vascular integrity and endothelial growth (Kim et al , ; Stone et al , ). Another point that made PKM2 particularly interesting is that it can be S ‐nitrosated and has been identified as a putative target of thioredoxin‐1 S ‐transnitrosation (Wu et al , ; Chung et al , ; Zhang et al , ).…”

Metabolic regulation of exercise-induced angiogenesis

“…However, when they need to sprout into avascular areas, they upregulate glycolysis even further and reducing EC glycolysis by deleting the glycolytic regulators Pfkfb3 (phosphofructokinase-2/frustcose-2,6-bisphosphatase isoform 3) or hexokinase 2 impairs EC migration and proliferation, resulting in impaired angiogenesis during development and under several pathological conditions ( 56 , 57 , 58 ). Beyond ensuring optimal energy provision, glycolytic enzymes (such as the pyruvate kinase muscle isoenzyme PKM2) also prevent cell cycle arrest during angiogenesis ( 59 ). ECs do not require mitochondrial ATP production for angiogenesis, but rather use their mitochondria to maintain NAD + /NADH balance ( 60 ) and as a hub for macromolecule synthesis during proliferation.…”