## 3 Molecular Changes in PVH Secondary to MMVD
### Endothelin 1
\begin{table}
\begin{tabular}{c c c c c c} \hline \hline \multirow{2}{*}{**Source**} & \multirow{2}{*}{**Tissue**} & \multirow{2}{*}{**Biomarker [Unit]**} & \multirow{2}{*}{**Control Group**} & \multicolumn{2}{c}{**MMVD**} \\ \cline{5-6}  & & & & **MMVD (PH+)** & **MMVD (PH\(-\))** \\ \hline \multicolumn{6}{c}{Endothelin and endothelin’s receptors} \\ \hline
[55] & Blood (plasma) & Et [pg/mL] & 17.8 (15.0–19.2) & 20.6 (17.2–23.1) & **n/a** \\ \hline
[71] & Lung & ET [\(-\)] & n/a &
\begin{tabular}{c} 3-fold increase in the \\ concentration \\ \end{tabular} & **n/a** \\ \hline
[71] & Lung & ET, B [\(-\)] & n/a &
\begin{tabular}{c} 3-fold increase in the \\ concentration \\ \end{tabular} & **n/a** \\ \hline \multicolumn{6}{c}{Vascular endothelial growth factor and VEGF’s receptors} \\ \hline
[55] & Blood (plasma) & VEGF [pg/mL] & 33.1 (29.7–36.9) & 81.2 (73.3–96.2) & **n/a** \\ \hline
[71] & Lung & VEGF [\(-\)] & n/a &
\begin{tabular}{c} 3-fold increase in the \\ concentration \\ \end{tabular} & **n/a** \\ \hline
[71] & Lung & VEGFR [\(-\)] & n/a &
\begin{tabular}{c} 3-fold increase in the \\ concentration \\ \end{tabular} & **n/a** \\ \hline \multicolumn{6}{c}{Oxide nitric} \\ \hline
[95] & Blood (plasma) & NO [μM] & n/a & 25.88 (15.08–36.71) & **n/a** \\ \hline \multicolumn{6}{c}{Serotonin value, expression of the receptors, and associated protein} \\ \hline
[55] & Blood (plasma) & SRT [ng/mL] & 26.1 (21.0–30.7) & 26.6 (22.4–30.5) & **n/a** \\ \hline
[96] & \multirow{2}{*}{Blood} & plasma & SRT (ng/mL) & 2.92 (1.76–7.50) & 1.75 (1.19–2.72) & 1.23 (0.27–4.23) \\ \cline{3-6}
[96] & & Platelet & \begin{tabular}{c} SRT [ng/109 \\ platelets] \\ \end{tabular} & \
\begin{tabular}{c} 179.73 \\ (102.37–352.24) \\ \end{tabular} & 135.11 (21.21–312.22) &
\begin{tabular}{c} 325.99 \\ (96.84–407.66) \\ \end{tabular} \\ \hline
[44] & Lung &
\begin{tabular}{c} TPH1 [ppa] \\ \end{tabular} & 0.86 \(\pm\) 0.19 & \(8.07\pm 0.73\) & \(5.43\pm 0.34\) \\ \cline{3-6}
[44] & &
\begin{tabular}{c} SERT [ppa] \\ \end{tabular} & 0.58 \(\pm\) 0.05 & \(9.87\pm 0.43\) & \(4.56\pm 0.44\) \\ \cline{3-6}
[97] & &
\begin{tabular}{c} 5 HT2A [ppa] \\ \end{tabular} & 1.48 \(\pm\) 0.11 & \(7.06\pm 0.83\) & \(45\pm 0.46\) \\ \cline{3-6}
[96] & & ERK [ppa] & 0.80 \(\pm\) 0.2 & \(7.78\pm 0.35\) & \(1.61\pm 0.47\) \\ \cline{3-6}  & &
\begin{tabular}{c} pERK [ppa] \\ \end{tabular} & 0.00 \(\pm\) 0.0 & \(6.61\pm 0.85\) & \(\mathbf{0.00\pm 0.00}\) \\ \hline
[44] & Lung &
\begin{tabular}{c} TPH-1 [rpe] \\ \end{tabular} & 2.33 (0.58–4.09) & 1.56 (0.68–5.08) & 1.59 (0.52–5.43) \\ \cline{3-6}
[94] & Lung &
\begin{tabular}{c} SERT [rpe] \\ \end{tabular} & 1.14 (0.09–3.10) & 1.49 (0.24–1.69) & 0.46 (0.04–1.00) \\ \cline{3-6}
[97] & & \
\begin{tabular}{c} 5-HTR2A [rpe] \\ \end{tabular} &
\begin{tabular}{c} 4.40 \\ (0.97–10.75) \\ \end{tabular} & 3.15 (2.36–8.88) & 2.59 (1.12–9.46) \\ \cline{3-6}
[97] & & ERK1/2 [rpe] & 1.74 (0.68–6.37) & 2.16 (1.04–4.29) & 1.41 (0.72–5.38) \\ \cline{3-6}  & & pERK1/2 [rpe] & 0.72 (0.13–2.01) & 0.21 (0.07–2.59) & 1.02 (0.35–4.09) \\ \hline
[95] & \multirow{2}{*}{Arte series} & TPH-1 [rpe] & 0.65 (0.49–1.12) & 1.85 (0.51–2.95) & 0.81 (0.29–4.09) \\ \cline{3-6}  & & SERT [rpe] & 0.23 (0.14–0.39) & 0.40 (0.04–0.74) & 0.14 (0.04–0.63) \\ \cline{3-6}  & & 5-HTR2A [rpe] & 0.68 (0.44–1.00) & 1.58 (0.50–2.57) & 0.99 (0.37–4.67) \\ \cline{3-6}  & & ERK1/2 [rpe] & 0.86 (0.73–1.04) & 1.04 (0.48–4.15) & 0.81 (0.54–4.23) \\ \cline{3-6}  & & pERK1/2 [rpe] & 0.61 (0.35–0.89) & 0.56 (0.10–2.87) & 0.45 (0.11–2.26) \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Values and changes; endothelin, VEGF, nitric oxide AND serotonin in healthy dogs and dogs with MMVD (PH \(-\)/+). (ppa—The average percentage of positive areas, rpe—The relative protein expression).