Abstract Body (Do not enter title and authors here): Background: Colorectal cancer (CRC) patients and survivors, irrespective of treatment received, have increased rates of hypertension and diseases of vascular remodeling compared to those without cancer. Prior literature demonstrates endothelial dysfunction and smooth muscle cell (SMC) plasticity in the localized CRC tumor microenvironment, but it is unknown if the cancer itself contributes to more global vascular changes in patients.
Hypothesis: CRC independently leads to vascular remodeling.
Methods: Age and sex-matched C57BL/6J mice were compared to spontaneous CRC mice with heterozygous loss-of-function of adenomatous polyposis coli (APC^Min+/-). A metastatic model using orthotopic liver injections of a syngeneic CRC cell line (MC38) was also compared to sham liver implantations. Endothelial and SMC functional testing were performed using ex vivo carotid arteries treated with phenylephrine, acetylcholine (Ach), and sodium nitroprusside (SNP). Stress-strain testing was performed on ex vivo thoracic aortic rings subjected to progressive tension. Assessment of collagen and elastin content in these vessels was also performed using Picrosirius Red and Verhoeff-Van Gieson, respectively.
Results: APC^Min+/- mice have reduced endothelial dependent dilation (EDD) after treatment with ACh (Peak EDD 94.15 ± 6.8 % vs. 79.35 ± 14.44 %, P<0.05), and increased aortic intrinsic mechanical wall stiffness (Elastic Modulus 3172 ± 1215 kPa vs 6890 ± 2284 kPa, P<0.05). Vessels from APC^Min+/- mice had increased collagen content (0.31± 0.12 % vs 0.5 ± 0.08 %, P<0.05) and lower elastin content (0.59 ± 0.06 % vs 0.5 vs 0.09 %, P < 0.05).
The metastatic CRC model conversely suggested a pattern of reduced endothelium independent dilation (EID) after vessels were treated with SNP (Peak EID 91.90 ± 9.8 vs 87.49 ± 4.8, P>0.05) as well as increased aortic intrinsic mechanical wall stiffness (Elastic Modulus 3274 ± 975 kPa vs 5527 ± 2277 kPa, P<0.05). Collagen content was increased (0.6% ± 0.11 vs 0.68% ± 0.11 P< 0.05), and elastin content decreased (0.6% ± 0.05 vs 0.57% ± 0.07 p>0.05).
Conclusion:
Spontaneous and metastatic models of CRC both demonstrated increased vascular stiffness and adverse remodeling. Murine models differed in vascular functional testing for EDD and EID, suggesting possible roles for both endothelial and SMCs in this remodeling process. Ongoing work is focused on defining secretome differences to further clarify signaling drivers of these observed changes.