Capillary Rarefaction in Obesity and Metabolic Diseases—Organ-Specificity and Possible Mechanisms

Figures

• 

  Figure 1. Consequences of obesity-induced capillary rarefaction on tissue function. White adipose tissue (WAT), brown adipose tissue (BAT), chronic kidney disease (CKD).

• 

  Figure 2. Regulation of vascular endothelial growth factor A (VEGFA)/ vascular endothelial growth factor receptor 2 (VEGFR2) signaling. (a) Placental growth factor (PlGF), VEGFB and VEGFA compete for binding to VEGFR1. VEGFA has ten times higher binding affinity to VEGFR1 than to VEGFR2 (reviewed in Reference [71]). (b) Binding of VEGFB to VEGFR1 displaces VEGFA and increases its bioavailability for binding to VEGFR2, which then induces angiogenic signaling via VEGFR2 activation. (c) Binding of PlGF to VEGFR1 increases angiogenesis both by displacing VEGFA and making it available for VEGFR2-binding and by activating PlGF’s own, albeit weaker, angiogenic signaling via VEGFR1 [77]. (d) Neuropilin-1 (NRP1) binds to VEGFA and presents it to VEGFR2, which enhances VEGFA/VEGFR2 signaling (reviewed in Reference [78]). (e) Binding of Angiopoietin 1 (ANGPT1) to its receptor TIE2 on endothelial cell (EC) surface activates signaling complex formation and recruits vascular endothelial protein tyrosine phosphatase (VE-PTP) to EC-EC junctions, which reduces VEGFR2 activity (reviewed in Reference [79]).

• 

  Figure 3. Endothelial regulation of adipose tissue (AT) phenotype. Factors such as diet-induced obesity [8], reduced vascular density due to a loss of Vegfa [8] or an increase in the anti-angiogenic isoform VEGFA165b may cause whitening of AT. On the other hand, increased vascular density due to Vegfa [74,75,83,84] or Vegfb [81] overexpression or Vegfr1 ablation [82] can induce browning of WAT in mice. Interestingly, the suppression of Vegfa expression in mice also led to a browning phenotype in WAT, suggesting that further studies are required to conclude the exact role of VEGFA in this phenomenon. Recently, endothelial protein argonaute-1 (AGO1) suppression was also shown to increase vascular density and AT browning [85].