Acute Lysyl Oxidase Inhibition Augments Cutaneous Vasoconstriction in Normotensive, but not Hypertensive, Men and Women
Authors: Craighead Daniel Harrison , Santhanam Lakshmi , Alexander Lacy Marie 
Published: November 2023

Hypertension in a highly prevalent chronic disease characterized by pathological remodeling of the vasculature. Lysyl oxidase and the lysyl oxidase like (LOXL) 1–4 proteins are putative targets that contribute to vessel remodeling in hypertension. The lysyl oxidase family of proteins catalyzes the cross‐linking of collagen fibers, increasing vessel stiffness. Upregulation of lysyl oxidase and LOXL 1–4 contributes to vascular remodeling in animal models, however in vivo human research is scarce due to the risk of aortic dissection with prolonged systemic lysyl oxidase inhibition. The cutaneous microvasculature is an easily accessible vascular bed that is representative of generalized microvascular function. Hypertension‐associated changes in vessel structure and function are observable in the cutaneous microvasculature. Additionally, intradermal microdialysis facilitates localized delivery of compounds to the skin, free of systemic effects. Therefore, the cutaneous microvasculature is a safe and appropriate vascular bed to examine human lysyl oxidase inhibition in vivo. Our objective was to inhibit lysyl oxidase and LOXL 1–4 in the cutaneous microvasculature to delineate the role of lysyl oxidase in microvascular dysfunction associated with hypertension. Four intradermal microdialysis fibers were placed in the forearm of 10 young (age: 24±1 y, MAP: 87±2 mmHg), 10 middle‐aged normotensive (age: 50±2 y, MAP: 84±1 mmHg), and 10 hypertensive (age: 53±2 y, MAP 112±2 mmHg) men and women. Two sites were perfused with β‐aminopropionitrile (BAPN) to inhibit lysyl oxidase and LOXL 1–4. The other two sites were perfused with lactated Ringer's to serve as control. One control and one BAPN site were perfused with increasing doses of norepinephrine (NE: 10−12–10−2M) to examine vasoconstrictor function. The other two sites were perfused with increasing doses of sodium nitroprusside (SNP: 10−8–10−1.3M) to examine smooth muscle vasodilator reactivity. Red cell flux was measured via laser Doppler flowmetry and normalized to cutaneous vascular conductance (CVC: flux•MAP−1). SNP data were expressed as absolute CVC while NE data were expressed as a percent change from baseline (%CVCbaseline). Data were pharmacologically curve modeled as four parameter logistic regressions and the LogEC50's compared to determine a change in sensitivity. Sensitivity to SNP was unaltered in young (control: −4.7, BAPN: −3.7; p=0.11), normotensive (control: −3.2, BAPN: −3.6; p=0.78), and hypertensive (control: −2.1, BAPN: −2.0; p=0.99) groups with lysyl oxidase inhibition. Lysyl oxidase inhibition increased sensitivity to NE in the young (control: −6.0, BAPN: −7.1; p=0.03) and normotensive (control: −4.8, BAPN: −7.0; p=0.01), but not hypertensive (control: −6.0, BAPN: −6.1; p=0.79) groups. These results suggest that acute inhibition of lysyl oxidase augments NE‐mediated cutaneous vasoconstriction in men and women with normal, but not high, blood pressure. The cutaneous microvasculature was a safe and appropriate model for this first‐step in vivo human research on the vascular effects of lysyl oxidase inhibition.

Support or Funding Information

ACSM Foundation Predoctoral Fellowship, NIH HL093238‐7