Surgical bypass grafting with autogenous vein for peripheral arterial occlusion remains the most durable option in patients with advanced peripheral arterial disease (PAD). However, de novo occlusions in the bypass graft represent significant challenges to the long-term success of bypass grafting.
The pathophysiology of vein bypass graft failure is a combination of acute vascular injury response, progression of atherosclerotic disease, and hemodynamic adaptation of the vein to arterial forces.
The BWH Division of Vascular and Endovascular Surgery is uniquely situated amidst a clinically active, integrated cardiovascular center which enables us to engage in clinical, translational and basic science research into the pathophysiology and treatment of peripheral bypass graft failure. We seek to address the interplay and contribution of multiple factors to the development and progression of vein graft disease:
An additional focus of the lab is on the molecular mechanisms of hypertension, particularly in the setting of pregnancy.
We have shown that overexpression of SVV, which is upregulated in cancer, is associated with protection from cytokine-induced apoptosis in cultured endothelial and vascular smooth muscle cells; conversely, overexpression of a dominant negative SVV construct directly induces apoptosis in these cells. Furthermore, SMC proliferation was increased by adenoviral transfer of SVV and reduced by expression of the dominant negative form. Using an in vivo model of vein graft disease, SMC proliferation and apoptosis (7 days), as well as wall thickness (30 days), were modified by adenoviral-mediated SVV expression. Adventitial angiogenesis was regulated by the SVV-expressing constructs in a fashion parallel to wall thickness changes.
We are currently working on delivery of specific SVV inhibitors and investigating their effects on SMC and EC phenotypes in vitro and in in vivo models of vascular injury.
Normal pregnancy is associated with reduction in vascular resistance and arterial pressure. These beneficial hemodynamic changes do not occur in women with preeclampsia; instead severe increase in blood pressure is observed; however, the vascular mechanisms involved are unclear. Reduction in uterine perfusion pressure and the ensuing placental ischemia/hypoxia trigger the release of placental factors such as TNF-α and reactive oxygen species. We test whether increases in placental factors lead to endothelial cell dysfunction and reduction in vasodilator substances such as nitric oxide (NO), prostacyclin (PGI2) and EDHF. The placental factors may also increase the release of contracting factors such as endothelin and thromboxane, which could increase [Ca2+]i and stimulate Ca2+-dependent contraction, or increase the activity of protein kinases, and enhance the myofilament sensitivity to [Ca2+]i and smooth muscle contraction. The decreased endothelium-dependent vascular relaxation and increased vascular contraction represent plausible causes of the increased vascular resistance and arterial pressure in preeclampsia.
High salt diet is associated with increased vascular resistance and arterial pressure in salt-sensitive individuals. In normal individuals, high salt diet does not increase the arterial pressure, suggesting possible vascular protective mechanisms. Endothelin-1 (ET-1), a potent vasoconstrictor, activates ETA and ETB receptors. Although the role of ETA receptors in vascular contraction and hypertension has been studied, the importance of ETB receptors in modulating the vascular function and arterial pressure particularly during high salt diet is unclear. In this project we test the possibility that normally during high salt diet an increase in ET-1 production and enhancement of ETA-mediated vascular contraction are counterbalanced by enhanced ETB-mediated vascular relaxation pathways, thus preventing excessive increases in vascular resistance and arterial pressure. These studies should help understand the vascular protective mechanisms during high salt diet in normal individuals. The studies will also shed light on the pathophysiological basis of the increased vascular resistance in salt-sensitive forms of hypertension.
We have undertaken a multidisciplinary, prospective approach to investigate the role of inflammation and insulin resistance in patients with PAD, including those with end-stage disease requiring lower extremity revascularization. To determine if inflammation and insulin resistance contribute to the functional and clinical consequences of PAD, we are involved in several studies, including a prospective case-control study correlating baseline inflammatory markers in with subsequent development of PAD. Patients undergoing lower extremity bypass surgery will also be included to determine if inflammatory markers and insulin resistance correlate with clinical events or with graft remodeling, as determined by ultrasound or MRI.
Through these studies, we hope to identify potential therapeutic targets for the early identification, amelioration and treatment of the functional and clinical consequences of PAD.
We have shown that baseline serum levels of C-reactive protein (CRP), an inflammatory marker, are elevated in patients undergoing lower extremity bypass surgery and that elevated levels correlate with postoperative cardiovascular and graft-related events. Furthermore, vein grafts in patients with elevated CRP levels demonstrate less positive lumen remodeling in the first month after bypass surgery, which is dependent on shear stress. We have also shown that CRP is detectable by immunohistochemistry in the deep media and adventitia of failing vein bypass grafts. Exposure of VSMCs to exogenous human CRP leads to increased gene and protein expression of platelet derived growth factor receptor beta (PDGFRβ) and increased phosphorylation of the receptor. These changes correlate with enhanced chemotaxis of VSMCs to PDGF-BB.
We are currently screening several novel anti-inflammatory compounds in VSMCs and ECs to determine if pharmacologically modulating inflammation will alter vascular cell phenotype.
Our work is supported by NIH (HL-075771, HL-65998, HL-085157, HL-070659).