Introduction: Pulmonary arterial hypertension (PAH) is a disease of progressive pulmonary vascular remodeling and obliteration with poor prognosis despite current therapies. Outcomes in PAH might be improved by earlier detection to permit therapy before irreversible loss of pulmonary vessels. The histology of remodeled lung vessels in human and experimental pulmonary hypertension (PH) exhibits increased expression of angiogenic growth factors and resembles dysregulated angiogenesis. We sought to validate VEGF-A as a molecular imaging marker of pulmonary vascular remodeling in experimental PH.
Hypothesis:89Zr-bevacizumab, a radiolabeled anti-VEGF-A antibody, can detect pulmonary vascular remodeling via PET-CT imaging in experimental models of PH.
Methods: Experimental PH was induced in rats with 3 weeks of treatment with SU5416 and hypoxia (SU-Hx) treatment followed by 3 weeks of normoxia, or by treatment with monocrotaline (MCT) for 3 weeks. VEGF-A expression was examined by immunohistochemistry (IHC) in lung tissues of rats with PH, and explanted lungs of PAH patients. Rats with or without PH were injected with 0.2 mCi/200 ug of 89Zr-bevacizumab i.v. and scanned sequentially over 7 d. Sectioned lungs were analyzed by autoradiography and immunofluorescence.
Results: IHC using 3 distinct anti-VEGF-A antibodies revealed elevated VEGF-A expression in the intima and media of small pulmonary arterioles from PAH patients and SU-Hx rats. In vivo PET-CT imaging and ex-vivo autoradiography demonstrated enhanced 89Zr-bevacizumab retention in peripheral lung fields of SU-Hx rats vs. controls. Immunofluorescence confirmed enhanced retention of 89Zr-bevacizumab in the intima and media of remodeled small arterioles of SU-Hx rats.
Conclusions: VEGF-A is a potential molecular imaging target, and 89Zr-bevacizumab is a potential PET molecular imaging probe for the non-invasive detection of pulmonary vascular remodeling in PAH.