The Endothelial Landscape and Its Role in Von Hippel–Lindau Disease

Abstract

Von Hippel–Lindau disease (VHL) is a rare hereditary disease characterized by the predisposal to develop different types of highly vascularized tumors. VHL patients carry a VHL mutation that causes partial lack of functional VHL protein (pVHL) in all cells, and a total lack thereof in cells harboring a second hit mutation. Absence of pVHL generates a prolonged state of pseudo-hypoxia in the cell due to accumulation of hypoxia inducible factor, an important transcription factor regulating pro-tumorigenic genes. The work here presented focuses on characterizing the endothelium of VHL patients, by means of blood outgrowth endothelial cells (BOECs). Transcriptome analysis of VHL-derived BOECs, further supported by in vitro assays, shows that these cells are at a disadvantage, as evidenced by loss of cell adhesion capacity, angiogenesis defects, and immune response and oxidative metabolic gene downregulation, which induce oxidative stress. These results suggest that the endothelium of VHL patients is functionally compromised and more susceptible to tumor development. These findings contribute to shedding light on the vascular landscape of VHL patients preceding the second hit mutation in the VHL gene. This knowledge could be useful in searching for new therapies for these patients and other vascular diseases.

Blockade of β2-Adrenergic Receptor Reduces Inflammation and Oxidative Stress in Clear Cell Renal Cell Carcinoma

“…We have recently demonstrated that ECs from VHL patients in heterozygote condition Vhl (+/−) show an increase in ROS due to the downregulation of enzymes in charge of ROS processing compared with control cells [16]. In this manuscript, we show (Figure 2) that the amount of ROS species quantified in VHL-ccRCC primary cultures and 786-O decreased in a significant manner following β2-blockers treatment (propranolol and ICI, respectively).…”

“…According to previous RNAseq results comparing VHL-ECs versus healthy ECs, ref. [16] ECs from VHL patients showed an increase in the amount of ROS due to the downregulation of enzymes in charge of ROS processing. Hence, we measured the amount of ROS from primary cultures of VHL-ccRCC and from 786-O cells before and after treatment with β-blockers.…”

“…In the same line, a recent RNAseq analysis of endothelial cells (ECs) from VHL patients (Vhl+/−) compared to ECs from healthy donors showed the downregulation of genes involved in reactive oxygen species (ROS) detoxification and NF-κB/p65 pathways [16].…”

The Role of VHL in the Development of von Hippel-Lindau Disease and Erythrocytosis

“…VHL-R167Q expressing RCCs are associated with a poor survival [90]. It has been shown that the endothelium of VHL patients is functionally compromised and more susceptible to tumor development [119]. Specific VHL mutations have been associated with defective blood vessel formation.…”

The Clinical and Molecular Features in the VHL Renal Cancers; Close or Distant Relatives with Sporadic Clear Cell Renal Cell Carcinoma?

“…ccRCCs are hypervascular tumors, and the main driving factor in tumor progression is represented by HIF overexpression and upregulated downstream effectors, above all VEGF [ 12 ]. The endothelium of VHL-deficient patients is highly dysfunctional, displaying altered cell adhesion, angiogenesis, migration, immune response, cell metabolism, and ROS homeostasis [ 101 ].…”