Rat Model of Parkes Weber Syndrome.

The Parkes Weber syndrome is a congenital vascular malformation, characterized by varicose veins, arterio-venous fistulas and overgrown limbs. No broadly accepted animal model of Parkes Weber syndrome has been described. We created side-to-side arterio-venous fistula between common femoral vessels with proximal non-absorbable ligature on common femoral vein limiting the enlargement of the vein diameter in Wistar rats. Contralateral limb was sham operated. Invasive blood pressure measurements in both iliac and inferior cava veins were performed in rats 30 days after fistula creation. Tight circumference and femoral bone length were measured. Histopathology and morphology of soleus muscle, extensor digitorum longus muscle, and the common femoral vessel were analyzed. 30 days following arterio-venous fistula creation, a statistically significant elevation of blood pressure in common iliac vein and limb overgrowth was observed. Limb enlargement was caused by muscle overgrowth, varicose veins formation and bone elongation. Arterio-venous fistula with proximal outflow limitation led to significant increase of femoral vein circumference and venous wall thickness. Our study indicates that the described rat model mimics major clinical features characteristic for the human Parkes Weber syndrome: presence of arterio-venous fistula, venous hypertension and dilatation, varicose veins formation, and the limb hypertrophy. We reveal that limb overgrowth is caused by bone elongation, muscle hypertrophy, and venous dilatation. The newly established model will permit detailed studies on the mechanisms underlying the disease and on the efficacy of novel therapeutic strategies for the Parkes Weber syndrome treatment

Difference in bone lengths in non-operated animals (i.e. the value of the length of the right femoral bone subtracted from the left femoral bone; left grey column, n = 3 bone pairs), and operated animals (i.e., value of the length of femoral bone of sham-operated limb subtracted from the length of femoral bone of the limb with AVF, n = 11 bone pairs).

<p>Difference in bone lengths in non-operated animals (i.e. the value of the length of the right femoral bone subtracted from the left femoral bone; left grey column, n = 3 bone pairs), and operated animals (i.e., value of the length of femoral bone of sham-operated limb subtracted from the length of femoral bone of the limb with AVF, n = 11 bone pairs).</p

Morphometric analysis of lower limb veins—difference between sham-operated limbs (grey columns, n = 9) and limbs with AVF (black columns, n = 9).

<p>Morphometric analysis of lower limb veins—difference between sham-operated limbs (grey columns, n = 9) and limbs with AVF (black columns, n = 9).</p

Venous pressure in sham-operated limbs (grey column, n = 13) and limbs with AVF (black column, n = 13).

<p>Venous pressure in sham-operated limbs (grey column, n = 13) and limbs with AVF (black column, n = 13).</p

Muscle overgrowth in hind limb with AVF—difference in EDL and SOL muscles weights of sham-operated limbs (grey columns, n = 14) and limbs with AVF (right columns, n = 14).

<p>Muscle overgrowth in hind limb with AVF—difference in EDL and SOL muscles weights of sham-operated limbs (grey columns, n = 14) and limbs with AVF (right columns, n = 14).</p

Limb enlargement (panel A) and tight circumference of sham-operated limbs (grey column, n = 14) and limbs with AVF (black column, n = 14) measurement (panel B).

<p>Limb enlargement (panel A) and tight circumference of sham-operated limbs (grey column, n = 14) and limbs with AVF (black column, n = 14) measurement (panel B).</p

Femoral blood vessels morphology () in sham-operated limbs (A, C) and limbs with AVF (B, D).

<p>Panels A, B—hematoxylin and eosin stained cryosections; panels C, D—Masson’s trichrome stained cryosections. White arrow indicates the vein, asterisk–the artery. Scale bar: 500μm</p

Number and area of muscle fibers, and connective tissue area in EDL muscle.

<p>A difference between sham-operated (grey column; n = 9) and limbs with AVF (black column; n = 11).</p