Acute Reductions in Blood Flow and Shear Stress Induce Platelet-Derived Growth Factor-A Expression in Baboon Prosthetic Grafts

Abstract

Abrupt reductions in fluid shear stress induce subendothelial smooth muscle cells (SMCs) to proliferate in experimental prosthetic grafts. Platelet-derived growth factor (PDGF), an important SMC mitogen, is expressed by cultured endothelial cells and modulated by shear stress. We hypothesized that this growth factor would be modulated by changes in shear stress in vivo. Bilateral aortoiliac prosthetic grafts were implanted into five baboons. High flow was generated by construction of femoral arteriovenous fistulas on both sides. Two months later, one of the fistulas was ligated, reducing shear stress in the upstream graft by 78 +/- 6%. Four days after fistula ligation, all grafts were removed and analyzed. As previously reported, SMC proliferation in low-flow grafts exceeded that in high-flow grafts, although the neointimal area was similar. mRNA levels for PDGF-A were significantly increased in low-flow grafts compared with high-flow grafts. In situ hybridization and immunohistochemical studies localized the increased PDGF-A mRNA and protein to the luminal endothelium and subjacent SMCs. Abrupt reductions in blood flow and fluid shear stress may induce accelerated neointimal thickening by a PDGF-A-mediated mechanism, since endothelial expression of this gene is temporally and anatomically associated with neointimal SMC proliferation.

Focal Expression of Angiotensin II Type 1 Receptor and Smooth Muscle Cell Proliferation in the Neointima of Experimental Vein Grafts

“…These studies showed that reduced blood flow upregulated the PDGF gene, whereas increased blood flow exerted an opposite effect in nonhuman primate polymer vascular grafts. 26,33 These results clearly demonstrated that blood flow played a role in the regulation of mitogen expression in blood vessels.…”

“…For instance, lowered fluid shear stress, with reference to physiological blood shear stress, promoted SMC proliferation and intimal hyperplasia, whereas increased fluid shear stress prevented these evens in experimental polymer vascular grafts in nonhuman primates. 26,32,33 Investigations on human and animal arterial atherosclerosis have supported these observations. [1][2][3][4] However, how oscillatory, low, fluid shear stress and increased shear stress gradients differentially regulate vein graft remodeling remains to be investigated.…”

“…34 -42 For instance, altered fluid shear stress influences the activities of mitogen-activated protein kinases 43,44 and G proteins, 45 the production rate of prostacyclin, 46 the activities of growth factors, 26,33,35,47,48 and the morphology 49,50 and cytoskeletal structure 51 of endothelial cells. These changes have been implicated in the mediation of mechanical stress-related vascular atherogenesis.…”

Novel Therapies for Hemodialysis Vascular Access Dysfunction

“…Baboons have been used to study effects of hemodynamics and antithrombotic therapy on neointima development in AVGs (27,28) and to evaluate bioengineered grafts (29). However, baboon purchase and care is expensive, and there is significant public opposition to the use of nonhuman primates in research.…”

Hemodialysis Vascular Access Dysfunction

“…High sheer stress has been associated with vascular dilatation through inhibition of smooth muscle cell proliferation and high levels of nitric oxide release, whereas low sheer stress has been associated with smooth muscle cell proliferation and lack of vasodilatation [120][121][122][123] . Poor hemodynamic profiles could be a risk factor for neointimal hyperplasia development and poor venous dilatation, and the degree of luminal stenosis is dependent upon both the magnitude of neointimal hyperplasia and the capacity for vasodilatation or vasocontriction.…”