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Strassheim et al. Vessel Plus 2018;2:29 I http://dx.doi.org/10.20517/2574-1209.2018.44 Page 9 of 22

Figure 3. Extracellular ATP up regulates HIF-1a and HIF-2a transcription factors in pulmonary artery vasa vasorum endothelial cells.
A, B: ATP (10 μmol/L), applied to VVEC, results in activation of both HIF-1a and HIF-2a with distinct time courses. VVEC were serum
starved for 18 h and stimulated for indicated times. Nuclear fractions were subjected for Western blot analysis for HIF-1a, HIF-2a, and
lamin A/C expression; C: cells were stained for HIF-1a at 1 h post stimulation with ATP (10 μmol/L), with or without PI3K inhibitor, PI-103
pretreatment (0.5 μmol/L, 15 min). VVEC: vasa vasorum endothelial cells

phages [41,171-174] .

INFLAMMATION-DRIVEN ENDOTHELIAL DYSFUNCTION (ED) AS A MECHANISM OF VASCU-

LAR REMODELING: INVOLVEMENT OF GPCRS
Inflammatory stimuli, IL-1 or TNFa down-regulate eNOS, attenuate reparative angiogenesis, promote
EC apoptosis, and increase endothelial to mesenchymal transition (EMT) - all of which contribute to
ED [46,83,175,176] . TxA , acting on both ECs and VSMCs, is pathological in PH and inhibits VEGF- or FGF-
2
2-promoted angiogenesis [46,147-149,165] . By contrast, many PH protective GPCR agonists (apelin, PGI ) increase
2
1177
eNOS activity by phosphorylation of Ser or by increasing eNOS expression [50-52,177-179] . Some PH therapeu-
tics, apelin and sildenafil, increase recruitment of endothelial cell progenitors, thereby counteracting ED [180-184] .

THROMBOSIS AND PLATELET ACTIVITY CROSS TALK WITH VASCULAR INFLAMMATION AND
GPCR ACTION
Platelets from patients with the sub-form of PAH, due to thromboembolic PAH, exhibit increased reac-
tivity to thrombin, which stimulates the G /G-coupled protease activated receptor 1 (PAR1), promoting
q
i
VSMC proliferation [185,186] . Thrombin receptors exist on EC and have been reported to inhibit angiogenesis.

RV REMODELING AND FAILURE
Cardiac myocytes (CMs) are terminally differentiated cells. The compensatory cardiac hypertrophy is en-