Linked opening angle and histological and mechanical aspects of the proximal pulmonary arteries of healthy and pulmonary hypertensive rats and calves

Abstract

Understanding how arterial remodeling changes the mechanical behavior of pulmonary arteries (PAs) is important to the evaluation of pulmonary vascular function. Early and current efforts have focused on the arteries' histological changes, their mechanical properties under in vitro mechanical testing, and their zero-stress and no-load states. However, the linkage between the histology and mechanical behavior is still not well understood. To explore this linkage, we investigated the geometry, residual stretch, and histology of proximal PAs in both adult rat and neonatal calf hypoxic models of pulmonary hypertension (PH), compared their changes due to chronic hypoxia across species, and proposed a two-layer mechanical model of artery to relate the opening angle to the stiffness ratio of the PA outer to inner layer. We found that the proximal PA remodeling in calves was quite different from that in rats. In rats, the arterial wall thickness, inner diameter, and outer layer thickness fraction all increased dramatically in PH and the opening angle decreased significantly, whereas in calves, only the arterial wall thickness increased in PH. The proposed model predicted that the stiffness ratio of the calf proximal PAs changed very little from control to hypertensive group, while the decrease of opening angle in rat proximal PAs in response to chronic hypoxia was approximately linear to the increase of the stiffness ratio. We conclude that the arterial remodeling in rat and calf proximal PAs is different and the change of opening angle can be linked to the change of the arterial histological structure and mechanics.

Fig. 1.

The cross-sectional representations of arteries at stress-free state with opening angle (OA) < 180° (A), at stress-free state with OA > 180° (B), and at no-load state (C). L_i, L_o, and H are the lengths of inner and outer walls and the thickness of the sector, respectively. For other symbol definitions, see Calculations.

Fig. 2.

A representative histological image of PA (top right), a 2-layer representation of an arterial ring (bottom left), and the schematic plot for the uniaxial tests on the intact tissue and inner layer (bottom right). For symbol definitions, see Calculations.

Fig. 3.

Bland-Altman agreement analysis between the 2 measurements of OA from the 3-point measurement (OA₁) and from the geometry data (using Eq. 1; OA₂) for 40 calf main pulmonary arteries (MPAs) and right pulmonary arteries (RPAs).

Fig. 4.

Comparisons of opening angle (OA₁) from 3-point measurement between control and hypertensive groups of rat and calf for MPA (A) and RPA (B). Insets: representative images of the opened arteries. Open stars (☆) in the images of the opened PA rings indicate the side of the inner wall of PAs. Bars represent means ± SD. *P < 0.05.

Fig. 5.

Comparisons of the arterial wall thickness-to-inner diameter (ID) ratio between control and hypertensive groups of rat and calf MPA and RPA. Bars represent means ± SD. *P < 0.05.

Fig. 6.

Comparisons of outer layer thickness fraction between control and hypertensive groups in rat and calf for MPA (A) and RPA (B); n is the number of histological images with the left value in the bracket indicated for control group and the right one for hypertensive group. Insets: representative histological images of PAs across the arterial wall. Collagen and elastin appear red and black, respectively. Bars represent means ± SD. *P < 0.05.

Fig. 7.

Representative histological images of inner cross-sectional tissues from adult bovine MPA after collagen-rich layer was cut off (A), and the modeled relationship between modulus ratio (f_m) and outer layer thickness fraction (f_t) for control calf MPA group (solid line) and experimental results on MPAs of control adult bovines (circles) (B). Note that 2 data points are nearly coincident at f_t ≈ 0.45 and f_m ≈ 0.3.

Fig. 8.

Stiffness ratios (SRs) of the outer to inner layer of the MPA and RPA in both rat and calf predicted from model.

Fig. 9.

Relationship between SR and OA for rat MPA and RPA predicted from model.