A Compartment Model of VEGF Distribution in Humans in the Presence of Soluble VEGF Receptor-1 Acting as a Ligand Trap
Figure 2
Targeting Control VEGF-Secretion Rates (qTotalVEGF) for Basal Profile of Healthy Subject.
A. Steady-state sensitivity of plasma and interstitial concentrations of free VEGF (top and middle rows) and free sVEGFR1 (bottom row) to qTotalVEGF from normal tissue (y-axis) and calf (x-axis. VEGF isoforms were secreted at a ratio of VEGF121∶VEGF165 = 1∶10. Top/middle row: In absence of sVEGFR1 (qsR1 = 0; labelled ‘-sR1’), plasma free VEGF reached the targeted 1.5 pM at the control VEGF-secretion rates of qV,-Ctrl = (qTotalVEGF,Normal, qTotalVEGF,Calf) = (0.264,0.154) molecule/MD/s. The incorporation of sVEGFR1 expression (qsR1 = qsR1,Ctrl; labelled ‘+sR1’) raised plasma VEGF significantly (red arrow) but with negligible effects on interstitial VEGF. To keep plasma free VEGF at the targeted 1.5 pM, the control VEGF-secretion rates were redefined (green arrow) to be qV,+Ctrl = (qTotalVEGF,Normal, qTotalVEGF,Calf) = (0.1925,0.1155) molecule/MD/s. Grey and beige spheres mark the interstitial and plasma VEGF levels reached at qV,-Ctrl and qV,+Ctrl respectively. Bottom row: Despite sVEGFR1's role as a VEGF sink, free sVEGFR1 only changed inversely relative to free VEGF changes in the calf interstitum in the direction of increasing qTotalVEGF,Calf. Orange/black arrows indicate inverse/direct relation between sVEGFR1 concentrations and VEGF-secretion rates. B. Density of VEGF-VEGFR complexes changed in proportion to interstitial free VEGF levels with increasing qTotalVEGF. Bracketed percentages are VEGF-bound fractional occupancies of total VEGFR, averaged (range<0.3%) between normal and calf compartments. In figure: ‘+’ = control; ‘max’ and ‘min’ bound targeted ranges; ‘MD’ = myonuclear domain; ‘V121’ = VEGF121; ‘V165’ = VEGF165; ‘R1’ = VEGFR1; ‘sR1’ = sVEGFR1; ‘R2’ = VEGFR2.