The role of vasculature and angiogenesis in respiratory diseases

Abstract

In European countries, nearly 10% of all hospital admissions are related to respiratory diseases, mainly chronic life-threatening diseases such as COPD, pulmonary hypertension, IPF or lung cancer. The contribution of blood vessels and angiogenesis to lung regeneration, remodeling and disease progression has been increasingly appreciated. The vascular supply of the lung shows the peculiarity of dual perfusion of the pulmonary circulation (vasa publica), which maintains a functional blood-gas barrier, and the bronchial circulation (vasa privata), which reveals a profiled capacity for angiogenesis (namely intussusceptive and sprouting angiogenesis) and alveolar-vascular remodeling by the recruitment of endothelial precursor cells. The aim of this review is to outline the importance of vascular remodeling and angiogenesis in a variety of non-neoplastic and neoplastic acute and chronic respiratory diseases such as lung infection, COPD, lung fibrosis, pulmonary hypertension and lung cancer.

Keywords: COPD; COVID-19; ECFC; Endothelial mesenchymal transition (EndoMT); Fibrovascular interface; Intussusceptive angiogenesis; Pulmonary fibrosis; Respiratory diseases; Tumor angiogenesis; Vascular normalization.

Fig. 1

A Schematic of pulmonary angiogenesis by sprouting and intussusceptive angiogenesis. B Illustrations and microvascular corrosion casting depict the morphogenetic processes during the intussusceptive expansion

Fig. 2

Multi-resolution imaging of a COVID-19 autopsy lung, using hierarchical phase contrast tomography (HiP-CT) illustrates the vascular remodeling of the bronchial circulation COVID-19 patients. Microvascular changes in COVID-19 lungs: a Volume rendering of a representative hierarchical phase-contrast tomography (HiP-CT) slice shows the spatial heterogeneities of microischemia and fibrotic remodelling of the airways. Micro-CT-based 3D reconstruction of subsegmental pulmonary arteries (red) and airways (blue) showed (sub-)total arterial occlusion in COVID-19 lungs of early and late hospitalized patients compared to uninfected controls c Three-dimensional evaluation of microvascular corrosion casts by synchrotron radiation tomography microscopy illustrating the altered and increased alveolar vascularity in COVID-19 lungs

Fig. 3

Scanning electron micrographs of microvascular corrosion casting of an elastase-induced emphysema model in mice (left) and chronic smoke exposition (right) in a murine smoke chamber model depict the capillary loss in emphysema and a peribronchial vascular remodeling. In pulmonary hypertension, anti-CD31 positive vessels depicts a microvascular outgrowth which is a morphological characteristic of plexiform lesions (SEM in blue box). A schematic illustration shows the expansion of vascular plexus in pulmonary hypertension. Scanning electron micrographs of microvascular corrosion casting of a PH lungs shows a plexiform budding with a loss of vascular hierarchy

Fig. 4

A Schematic illustrates the fibrovascular interface in fibrotic lung diseases. B Scanning electron micrographs of microvascular corrosion casts illustrate the substantial architectural differences between the different injury patterns. Healthy control lung vasculature is characterized by thin-walled alveolar capillary plexuses aligned along the alveolar duct; UIP lungs demonstrate an aberrant vasculature with blunt, sinusoid-like vessels, without a clear vessel hierarchy, but instead high variability of vessel diameters and small vessel sprouts; NSIP lungs present with dense, tortuous dilated tufts of vessel formations in the alveolar septa and frequent intussusceptive pillars; AFE lungs resemble the appearance of the NSIP lungs with pronounced vascular alterations in the alveolar septa. Schematic illustration of morphomolecular motifs in histopathological subtypes of interstitial lung injury models

Fig. 5

A Scanning electron micrograph shows the cross-section of a human pulmonary adenocarcinoma. B Microvascular corrosion casting depicts the vascular architectural alterations in the before-mentioned pulmonary adenocarcinoma characterized by abnormal, tortuous blood vessels with a missing hierarchy. C Scanning electron micrograph of the microvascular corrosion casting in A549-NSCLC-xenografts shows an abnormal tumor vascularity with blind-ending vessels and elongations. D In bevacizumab-treated A549-NSCLC- xenografts, the tumor vascularity is restored to a “normalized” architecture. E The transient normalization window results in a higher vulnerability of cancer cells to cytotoxic agents and an improved perfusion of immune checkpoint inhibitors. F Effects of anti-angiogenic treatments on vascular morphology and angio-immunlogic switch