In this study, we validated the use of OPS and SDF imaging using a novel lightweight computer-controlled imaging sensor-based microscope. This results show that SDF imaging yielded higher-quality images, especially of blood samples of individuals residing at a high altitude. This study shows the differences in microcirculatory responses to different altitudes.
Microcirculation refers to arterioles and venules with diameters < 100 µm. Exchange of tissue fluid, blood, lymph, and substances in the tissue fluid occur at the microcirculatory level. Microcirculation is responsible for the transport of all blood-borne hormones and nutrients to tissues and mediates immune function and homeostasis [11]. Based on different classifications of microvascular function, capillaries can be divided into resistant capillaries, exchange capillaries, microvascular capillaries, and capacity capillaries. Capillaries are the primary mediators of exchange between the blood and tissue owing to their thin walls, high permeability, and large contact area, which decelerates blood flow (0.5–1.0 mm/s) [12].
Low arterial blood oxygen partial pressure (PaO2); low arterial blood oxygen saturation (SaO2); and hemorheological characteristics, including blood viscoelasticity, thixotropy, degeneration and aggregation of RBC, and platelet adhesion and aggregation, significantly contribute to circulation, especially microcirculation, in hypoxic environment such as that on the Qinghai-Tibetan plateau [13].
The physiological response to high-altitude chronic hypoxia involves an increase in the RBC count in microcirculation to compensate for the lack of oxygen in the atmosphere [14]. Our results show that RBC counts, hemoglobin levels, and hematocrit were significantly higher in individuals from Xining than from Nanjing. However, hypoxia exerts adverse effects on the body, resulting in changes in capillary and microvessel blood flow, including capillary contraction, a reduction in the diameter of fine arteries, and deceleration of capillary blood flow [15], concurrent with our results. Long-term chronic hypoxia potentially promotes capillary proliferation, especially of those in the brain, heart, and skeletal muscles. An increase in the density of capillaries can shorten the distance of blood oxygen dispersion to cells and increase cellular oxygenation. Deceleration of microcirculatory blood flow could be an adaptive response and might increase the tissue transit time of RBCs and improve oxygen diffusion. A prolonged course through the capillary network may enhance oxygen off-loading in the presence of a reduced partial pressure gradient between the capillary and mitochondria. Changes to the capillary wall might lead to the adherence and aggregation of WBCs. Increased permeability in capillaries and small veins is accompanied by an increase in blood density and viscosity. When WBCs adhere to capillary walls, capillary resistance is increased, and when coupled with RBC aggregation, blood flow is further decelerated. Under normal circumstances, the RBC surface is negatively charged; hence, RBCs repel each other and do not aggregate. However, capillary endothelial cell damage may occur in individuals residing at high altitudes; accordingly, the negative charge on the RBC surface can be reduced, the membrane composition and plasma proteins can be changed, and these alterations in blood flow can lead to increased RBC and platelet adhesion and aggregation, which may increase intravascular pressure, vascular permeability, plasma spillover, and spontaneous bleeding, leading to ecchymosis [16]. These changes in blood flow characteristics not only lead to microthrombosis and significantly reduce blood flow velocity but also reduce the frequency of gas exchange, slowing metabolite elimination. This potentially results in the accumulation of acidic products and a lower pH, which directly affects tissues, organs, and cell metabolism and causes serious cell degeneration, necrosis, and alterations in tissue organization. These changes directly affect the exchange of substances, switching time, and exchange rate. A modest increase in RBC and hemoglobin can increase the oxygen carrying capacity of blood and blood oxygenation, which is a compensatory mechanism. However, excessive RBC hyperplasia can increase blood viscosity and lead to blood flow resistance, thus reducing blood flow and increasing the load on the heart. Excessive RBC proliferation serves as an adaptation to hypoxic conditions on the plateau to enhance blood flow rate, cellular metabolism, and nutrient exchange as well as to increase the number of capillaries.
Herein, TVD, PVD, and PPV were significantly higher in individuals from Xining than among those from Nanjing. An increase in capillary density in the skeletal muscles has been observed not only in humans but also in animals residing on the plateau. Animal studies have shown that dogs and other animals on the plateau in chronic hypoxic conditions have increased capillary densities in both the myocardium and gray matter. Blood capillary hyperplasia decreases the distance of oxygen circulation between capillaries and tissues and improves tissue oxygen levels and cellular adaptive responses to hypoxia. Increased vascular density is the body's response to hypoxic environments and may involve recruitment or peripheral vascular angiogenesis [17]. Both chronic and acute hypoxia alter capillary density. Martin recorded the MFI and vascular density of 24 healthy volunteers who climbed from sea level to a plateau at an altitude of 5300 m, 14 of whom further climbed to a higher altitude (6400 m), and reported that the MFI in small blood vessels (< 25 µm, P < 0.0001) and secondary vessels (26–50 µm, P = 0.006) was significantly lower at either altitude than that at sea level and significantly higher at 6400 m than at 5300 m (P = 0.017 and 0.002, respectively). Additionally, the number of small blood vessels (< 25 µm) and secondary vessels (26–50 µm) decreased from 2.8 to 2.5 and 2.9 to 2.4, respectively. Herein, although the density of small blood vessels (< 25 µm) did not significantly increase, the number of secondary vessels (26–50 µm) significantly increased (1.68 ± 0.43 vs 2.27 ± 0.57 mm/mm2, P = 0.005), and vascular density at other altitudes also significantly increased (P < 0.001) [5].
Deceleration of blood flow results in a longer microcirculation perfusion time in tissues. Furthermore, improvement of the local pressure gradient can reduce oxygen diffusion between capillaries and mitochondria. Daniel et al. reported that individuals on a plateau presented a significant reduction in MFI during acute hypoxia and a significant increase in vascular density. The major mechanism underlying capillary hyperplasia is the upregulation of vascular endothelial growth factor (VEGF) [18], a specific glycoprotein that influences vascular endothelial cells; regulates almost all phenomena related to blood capillary hyperplasia, including gene expression in endothelial cells, degradation of the basement membrane, and endothelial cell migration and proliferation; and increases the permeability of microvascular endothelial cells. Furthermore, VEGF is significantly upregulated during septic shock [19]. This mechanism in endothelial cells in microvessels is the same in septic shock and hypoxia.
Sepsis is characterized by severe microvascular dysfunction and can cause septic shock [20]. Microvascular dysfunction during septic shock is associated with increased capillary permeability, which manifests as the destruction of the microvascular endothelial barrier (involving factors potentially associated with capillary leakage syndrome, e.g., endogenous pro-inflammatory cytokines, angiogenin 2, and VEGF) [21].