Keywords

1 Introduction

PH is defined as the mean pulmonary artery pressure (mPAP) is 20 mmHg or higher in the resting state. PH is an unwanted disease with the rising incidence rate and death rate, so the researchers pay more and more attention to explore the mechanism and effective treatment of PH (Hansmann 2017). The World Symposium on Pulmonary Hypertension (WSPH) divides PH into five groups according to its symptoms, pathological mechanisms, hemodynamic features, and treatment methods: Group 1: pulmonary arterial hypertension (PAH); Group 2: PH due to left heart disease; Group 3: PH due to lung diseases and/or hypoxia; Group 4: PH due to pulmonary artery obstructions and Group 5: PH with unclear and/or multifactorial mechanisms. The latest PH clinical classification and its causes are presented in Table 1 (Simonneau et al. 2019). The main pathological characteristics of PH include pulmonary vascular contraction and remodeling, inflammation, and microthrombosis. Specially, pulmonary vascular remodeling is becoming more and more important in PH, but there is still a lack of the effective therapy for pulmonary vascular remodeling (Zhao et al. 2021). Endothelin-1, prostacyclin, and nitric oxide are three pathological factors involved in PAH based on the dysfunction of endothelial cells and have been taken as the directions to PAH treatment (Pulido et al. 2016). However, these immediate treatments can’t markedly improve the morbidity and the mortality of PH, except lung transplantation (Evans et al. 2021). With the progression of cellular and molecular biology, it is believed that the therapeutic targets for alleviating vascular remodeling, pulmonary contraction, and pulmonary inflammation would be constantly discovered.

Table 1 Updated clinical classification and causes of PH
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In addition, it is gradually recognized of the impacts of the changes on the pulmonary vascular microenvironment of PH, especially the role of the interactions between the cells of the pulmonary vascular wall in the development of PH (Pasha 2014). PH includes abnormalities of vascular cells (endothelial cells, smooth muscle cells, and fibroblasts) and inflammatory cells (Southgate et al. 2020). More and more reports are proved of the roles of endothelial cells (ECs), smooth muscle cells (SMCs), and fibroblasts, as well as platelets and inflammatory cells in PH (Stenmark et al. 2018). However, the role of the interaction between alveolar epithelial cells and other cells in PH is unclear. It should be furtherly explored whether alveolar epithelial cells are involved in pulmonary vascular remodeling, pulmonary vascular contraction, and pulmonary inflammation. The purpose of this review is focused on the roles of crosstalk between cells in the pathogenesis of PH and to explore the potential therapeutic targets to improve the survival rates.

2 Fundamental Pathogenesis in the Progression of PH

PH is a cardiopulmonary illness that can influence the pulmonary arterial and venous circulation and induce right ventricle hypertrophy (Hoeper et al. 2017; Kim and George 2019). The pathogenic factors of PH include pulmonary endothelial cell disorders, abnormal vascular wall cell proliferation, inflammation, and multiple gene mutations, which finally lead to right ventricular hypertrophy, cardio myocytes damage, and death (Makino et al. 2011; Tuder 2017; Montani et al. 2016) (Fig. 1). Despite different forms of PH exhibit diverse pathological mechanisms, the previous research results indicated that the crosstalks between the blood vessel wall cells (i.e., SMCs, fibroblasts, and Ecs) are the corporative features of the molecules and the cells involved in pulmonary vascular remodeling, pulmonary vascular contraction, and pulmonary inflammation (Pasha 2014). Therefore, exploring these molecular and cellular pathogenesis of PH will help to find more effective therapeutic targets to control the progression of PH.

Fig. 1
figure 1

Basic pathogenesis in the progression of PH. The basic pathogenesis of PH includes vasoconstriction, vascular remodeling, inflammation and gene mutation, which results in pulmonary arterial hypertension and right ventricular hypertrophy

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3 Pulmonary ECs Crosstalk with SMCs

3.1 EC Regulation of SMC Proliferation

ECs can adjust and control the vascular function. EC dysfunction means the imbalance between vasoconstrictors and vasodilators produced by EC, between activators and inhibitors of SMC growth and migration, and between proinflammatory and anti-inflammatory signals in the PAH (Perros et al. 2015). Specifically, when EC dysfunction, PAH has the following characteristics: pulmonary inflammation, accumulation of inflammatory cells, oxidative/nitrifying stress, changes in vascular cell viability, and proliferation (Evans et al. 2021; Huertas et al. 2014). These characteristics of PAH support the key role of EC dysfunction in the pathogenesis of PAH. It is worth exploring whether the proliferation of SMC is an inherent sign or is caused by the dysfunction of ECs. In the homeostasis of the pulmonary circulation, the interaction between EC and SMC plays an important role (Gao et al. 2016). Under a pathological status, the interaction of the two cells leads to an increase in pulmonary blood vessel tension, which in turn results in a series of pathological manifestations such as increased pulmonary artery pressure, vascular remodeling, and right ventricular hypertrophy (Guignabert et al. 2015). Hypoxia-induced mitogenic factor (HIMF) plays an important role in EC-SMC crosstalk. HIMF stimulated pulmonary artery ECs (PAECs) to generate and release high mobility group box-1 (HMGB1) by the regulation of autophagy and bone morphogenic protein receptor 2 (BMPR2), and finally made pulmonary artery smooth muscle cells (PASMCs) proliferation (Gao et al. 2016). Dysfunctional PAECs deliver a variety of mediators, for instance, platelet-derived growth factor-BB (PDGF-B), endothelin-1 (ET-1), chemokine 12 (CXCL12), and macrophage migration inhibitory factor (MIF), which can induce forkhead box M1 (FoxM1) expression in PASMCs and activate FoxM1-related to PASMCs proliferation, resulting in pulmonary vascular remodeling and PH (Dai et al. 2018). There is an evidence that ECs can communicate with SMCs through micro-RNA195 to regulate serotonin transporter (5-HTT) to induce the proliferation of SMCs (Gu et al. 2017). Previous studies have shown that the proliferative endothelial cell phenotype is the prominent feature of PAH. The studies suggested that changes in EC phenotype contribute to the occurrence of PAH (Awad et al. 2016). For example, long-term smoking can change the phenotype of human lung microvascular EC. Thereby, inducing EC apoptosis or inherited epigenetic EC dysfunction is related to pulmonary artery remodeling and PH (Petrusca et al. 2014). This crosstalk between ECs and SMCs leads to SMC proliferation and an increase in the thickness of the inner wall of blood vessels.

3.2 SMC Regulation of EC Proliferation and Migration

Recent studies provide a few fascinating findings of SMC regulation of EC proliferation. In SMC-EC co-culture, it was found that BMPR2 activated notch receptor 1 (Notch1) to induce EC proliferation (Miyagawa et al. 2019). Both cells required BMPR2 to produce type IV collagen to activate integrin-linked kinase and result in stabilization of presenilin 1 (PS1) and activation of Notch1. And Notch1 kept the EC proliferative capacity by fortifying mitochondrial mass and tempting 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3). Loss of Notch1 aggravated hypoxia-induced PH, which was related to damaged EC proliferation and regeneration, leading to loss of anterior capillary arteries (Miyagawa et al. 2019). This research offered the direct evidence that SMC promoted EC proliferation and rebirth to keep monolayer integrity and vascular homeostasis. Some factors released by SMC entice EC migration. The important factors mediating cell–cell communication are cytokines, chemokines, and cell surface receptors (Hwang 2013). New research reports indicated that exosomes were also significant mediators of cell–cell interactions. A lot of diverse molecules existed in exosomes can be absorbed by recipient cells (Jiao et al. 2018). There is an evidence that microRNA-143 (miR-143) plays an important role in PAH patients and PAH animal models. The exosome miR-143 secreted from PASMCs facilitated the migration of PAECs (Deng et al. 2015). This shows that the exosome-mediated intercellular communication between PASMC and PAEC is of significance in PH.

4 Pulmonary ECs Crosstalk with Non-SMCs

4.1 Fibroblasts

The EC-fibroblast crosstalk acts a specific role in the pathogenesis of PAH as well. Endothelial to mesenchymal transition (EndoMT) is involved in the pathogenesis of many human illnesses such as PAH (Jimenez and Piera-Velazquez 2016). ECs can turn into fibroblast-like cells through EndoMT and have an effect on PAH. ECs polarized fibroblasts into myofibroblasts by releasing ET-1and interleukin 6 (IL-6) and then obtained collagen and extracellular matrix proteins to accelerate pulmonary vascular remodeling (Thenappan et al. 2018; Evans et al. 2021). Adventitia fibroblasts take a part in pulmonary vascular remodeling by means of multiple mechanisms. For instance, the augment of myofibroblasts increased the rigidity of the extracellular matrix, which directly caused the activation of PAEC proliferation (Thenappan et al. 2018). Fibroblast-originated matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and 15-hydroxyeicosatetraenoic acid (15-HETE) can regulate PAEC proliferation (Liu et al. 2018). The secreted protein thrombospondin-1 (TSP1) in lung fibroblasts disrupted EC–fibroblasts interactions to promote vascular remodeling in PAH (Labrousse-Arias et al. 2016).

4.2 Pericytes

In PAH, the number of pericytes is reduced and pericyte-EC crosstalk is also attributed to pulmonary vascular remodeling. Abnormal pericyte recruitment contributes to the pathogenesis of PAH (Ricard et al. 2014). Studies have shown that Wnt family member 5A (Wnt5a) plays a key role in the crosstalk between pulmonary microvascular endothelial cells (PMVECs) and pericytes, and also contributes to pulmonary vascular remodeling in PAH. The recruitment of pericytes in small blood vessels needed Wnt5a produced by healthy PMVECs. But defects of Wnt5a in PAH PMVECs can cause persistent pulmonary hypertension and right heart failure after hypoxia recovery (Yuan et al. 2019). As a result, PMVECs lack of Wnt5a had a decreasing capacity to recruit pericytes and resulted in a loss of small blood vessels in PAH (Yuan et al. 2019). In addition, Pyruvate Dehydrogenase Kinase 4 (PDK4), which is a gene encoding a mitochondrial enzyme responsible for inhibiting glucose oxidation, is related to the excessive proliferation of pericytes in PAH and improved EC-pericyte crosstalk. The decrease of PDK4 contributes to promote EC-pericyte crosstalk (Yuan et al. 2016). Therefore, genes that regulate and control pericyte-EC crosstalk may become a new therapeutic target to cure the loss of small blood vessels in PAH.

4.3 Inflammatory Cells

The main structural change of PAH is pulmonary vascular remodeling (Liang et al. 2020). And there have been definite reports showing that inflammation plays a major pathogenic factor in pulmonary vascular remodeling (Oliveira et al. 2017). At the same time, the recruitment of inflammatory cells and EC proliferation play an equally important effect in the pathogenesis of PAH (Mumby et al. 2017). It can be seen that inflammatory cells and ECs are inseparable from the development of PAH (Kuebler et al. 2018). Hence, the role of inflammation in PAH is getting more and more attention. Cytokines and chemokines are certain to be the driving factors and contributing factors of the perivascular inflammation in PAH (Le Hiress et al. 2015). Macrophages and lymphocytes may be referred to the course of pulmonary blood vessel remodeling. The recruitment and accumulation of leukocytes were facilitated by granulocyte macrophage colony-stimulating factor (GM-CSF) (Sawada et al. 2014), CXCL12 (Dai et al. 2016), connective tissue growth factor (CTGF) (Pi et al. 2018), IL-6 (Van Hung et al. 2014), and leptin (Xue et al. 2017) released by activated ECs. Other factors released from accumulated leukocytes such as leukotriene B4 (LTB4) derived from macrophages can cause EC apoptosis (Tian et al. 2013), and MIF derived from T cell lymphocytes can cause inflammation of the EC and recruit inflammatory cells (Le Hiress et al. 2015).

5 Alveolar Epithelial Cells Crosstalk with SMCs

5.1 Alveolar Epithelial Cell Regulation of SMC Proliferation

Apart from damage and dysfunction of EC in the pathogenesis of PH, more and more people realize that the alveolar epithelial cells (AECs) play an equally significant role in the development of PH. Some studies found that the activation of endoplasmic reticulum stress after long-term high-altitude exposure accelerates the apoptosis of AECs, which may induce the occurrence and development of high-altitude pulmonary hypertension (Pu et al. 2020). CTGF over-expressed in epithelial cells activates the integrin-linked kinase (ILK)/glucose synthesis kinase-3β (GSK-3β)/β-catenin pathway, resulting in dysfunction of epithelial cell and PASMC remodeling, which finally leads to the occurrence of PH (Chen et al. 2011). Recently, it has also been found that AECs take part in the pulmonary vascular contraction and remodeling of hypoxic pulmonary hypertension (Wang et al. 2021). The function of alveolar epithelial cells is not only a component of gas exchange but also a vital barrier to protect the human body from harm. AECs can quickly repair and regenerate cells to restore a complete alveolar epithelial barrier and then respond to acute lung injury (Zhang et al. 2019). Alveolar type I (AT1) and alveolar type II (AT2) cells are two types of AECs. The main function of AT2 cells is to synthesize and secrete pulmonary surfactants. Furthermore, AT2 cells can be differentiated into AT1 cells in the homeostasis of the alveoli and the repair process after injury. The AT1 cells constitute the thin air-blood barrier, which is the epithelial component, and the coverage rate reaches 95% of the alveolar surface area (Chen and Liu 2020). According to previous reports, in hypoxic pulmonary hypertension (HPH), the response of pulmonary blood vessels to hypoxia was not like the expansion of blood vessels in the systemic circulation but vasoconstriction (Böger and Hannemann 2020). The alveoli will not make a rise in systemic pressure after being hypoxic, but only made an increase in pulmonary artery pressure. After the alveoli sense hypoxia, it was primarily felt on the alveolar capillary membrane. The alveolar capillary membrane is composed of epithelial and endothelial membranes on the alveolar wall. The hypoxia signal propagated from the alveolar capillaries to the small arteries and then caused the contraction of PASMCs (Hough et al. 2018). Both AECs and ECs show tolerance to hypoxia, but AECs were more sensitive (Wang et al. 2021). It was reported that hypoxia increased the concentration of reactive oxygen species (ROS) in AECs (Grimmer and Kuebler 2017). Hydrogen peroxide (H2O2) from AECs dependent on the ROS/superoxide dismutase 2 (SOD2) pathway regulated pulmonary vascular remodeling and contraction. In vitro, it was manifested that AECs not only facilitated the proliferation of PASMCs but also facilitated the proliferation of aortic artery smooth cells (AASMCs) in hypoxia (Wang et al. 2021). Therefore, the pulmonary vascular microenvironment formed by AECs and SMCs was involved in the remodeling and contraction of pulmonary vessels.

5.2 SMC Regulation of AEC Proliferation

In acute lung inflammation, the spread of this inflammation relied on the immunologic function of lung interstitial cells, for example, SMCs (Udjus et al. 2019). SMC released a mass of proinflammatory factors, for instance, cytokines (Tumor Necrosis Factor-alpha [TNF-α], IL-6), chemokines (Chemokine 8 [CXCL8]/Interleukin 8 [IL-8]/murine Chemokine 1 [CXCL1]), and growth factors (neuregulins [NRGs] and transforming growth factor alpha [TGFα]) (Tliba and Panettieri 2009). These inflammatory responses need a disintegrin and metalloproteinase 17 (ADAM 17)-mediated transactivation of ErbB receptors after the application of exogenous TGFα or NRG1. Transactivation of cells mediated by ErbB via binding to epidermal growth factor receptor (EGFR)/ErbB1 or ErbB3 and ErbB4 receptors and shed TGFα or NRGs. Furthermore, ErbB4 has developmental functions and is involved in the synthesis and proliferation of surface active substances in AECs. Therefore, in the pulmonary inflammation, decreased ADAM 17-mediated growth factor in SMC accelerated the transactivation of ErbB4 by means of NRGs, for example, NRG1 activation facilitated the proliferation of AECs and keeps the homeostasis of the cellular environment (Dreymueller et al. 2014). It is worth attention of the crosstalk between AECs and SMCs in pulmonary inflammation of PH.

6 Alveolar Epithelial Cells Crosstalk with Non-SMCs

6.1 Fibroblast

Idiopathic pulmonary fibrosis (IPF), pathologically common interstitial pneumonia, is a long-term disease with unclear etiology (Larson-Casey et al. 2020). The pathogenesis of the disease includes alveolar epithelial injury, abnormal vascular repair, and pulmonary vascular remodeling. The main complications of IPF patient survival include lung cancer and pulmonary hypertension. There were a lot of evidence that one of the important factors leading to IPF is the dysfunction and continuous damage of AECs (Lee et al. 2018; Wang et al. 2020). The migration, proliferation, and activation of mesenchymal cells are caused by active AECs and are accompanied by the formation of fibroblasts/myofibroblasts foci and excessive accumulation of extracellular matrix. Just like that DNA harm in AEC II resulted in osteopontin (OPN) expression via activating extracellular signal-regulated kinase (ERK)-dependent signaling pathways. The induced OPN boosts the proliferation of AEC II and the migration of fibroblasts (Kato et al. 2014). Therefore, the integrity of the alveolar epithelial barrier was ultimately maintained due to the interaction between AECs and fibroblasts, which indicated that crosstalk between AECs and fibroblasts will be closely associated with the development of PH.

6.2 Macrophages

Similarly, the interactions between AECs and macrophages play an equally important regulatory role in the development of pulmonary diseases (Young et al. 2016; Byrne et al. 2016). Macrophages are one of the important regulators of pulmonary inflammatory disease. Macrophages plasticity, specificity, and ability to interact with other cells make them a pivotal factor in the pathogenesis of pulmonary inflammatory disease (Wang et al. 2019). In addition, the crosstalk between macrophages and AECs is a key factor in the pathological process of pulmonary inflammation and fibrosis, which is directly attributed to the contact between macrophages and AECs. AT2 cells can secrete sonic hedgehog (Shh), and its signal transduction facilitated the secretion of OPN in macrophages. OPN acted on macrophages through autocrine or paracrine mode. And OPN fortified the expression of arginase-1 by means of activating the Janus kinase-2/transcription 3 (JAK2/STAT3) signaling pathway, and caused pulmonary fibrosis to occur (Hou et al. 2021). Similarly, the interaction between AECs and macrophages also plays an important role in regulating the progression of lung injury, which is becoming a new research hotspot. Exosomes from AECs can cause pulmonary inflammation and enable the migration and activation of macrophages. MicroRNA-92a-3p (miR-92a-3p) in AECs-derived exosomes mediated cellular communication between AECs and macrophages and facilitated the activation of macrophages by means of controlling Phosphatase and tensin homolog (PTEN) expression and adjusting the activation of nuclear factor-κB (NF-κB) signaling pathways (Liu et al. 2021). Therefore, the crosstalks between AECs and macrophages probably take part in PH by regulating pulmonary inflammation.

7 Macrophages Crosstalk with SMCs

The accumulation of inflammatory cells is an important feature in vascular injury during PAH. Inflammatory cells (T, B lymphocytes, mast cells, monocytes, and macrophages) take a key part in the PAH process. Macrophages are innate immune cells, composed of recruited/infiltrated monocytes, which are essential for keeping homeostasis and repairing ability. Polarized macrophages may be generally classified into three genres: classically activated macrophages (M1), alternating activated macrophages (M2), and regulatory macrophages (M2b) (Huang et al. 2020). So it is worth noting that macrophages are involved in the pathogenesis of PAH (Bordenave et al. 2020). Early recruitment and replacement activation of macrophages are of great significance in the pathogenesis of PAH (Bai et al. 2019). Macrophage-mediated inflammation is intricate, and the interaction between macrophages and PASMCs can regulate the internal microenvironment of the lung. In the co-culture of m2-macrophages and PASMC in direct contact, we understand that it facilitates the proliferation and migration of PASMC by relying on C-C chemokine receptor types 2/C-C chemokine receptor types 5 (CCR2/CCR5) (Abid et al. 2019). Furthermore, we found that M2b macrophages can also adjust the proliferation, migration, and apoptosis of PASMC by adjusting and controlling the phosphatidylinositol-3-kinase/protein kinase B/forkhead box protein O3a (PI3K/Akt/FoxO3a) pathway (Huang et al. 2020). Six-transmembrane protein of prostate 2 (Stamp2) has been reported to be an important anti-inflammatory protein in macrophages. The lack of Stamp2 can directly affect the interaction between macrophages and SMCs, resulting in aggravation of pulmonary hypertension caused by hypoxia (Batool et al. 2020). And a recent study showed that LTB4 (5-lipoxygenase [5-LO] metabolite) derived from macrophages plays an important effect in causing pulmonary vascular remodeling in PAH (Tian et al. 2013; Peters-Golden and Henderson 2007). 5-LO and LTB4 are related to the evolution of PAH (Peters-Golden and Henderson 2007). In the lung lesions of hPAH patients with Bmpr2 mutations, 5-LO-mediated inflammation similarly converts PAEC into a diseased neointimal phenotype. In rats and patients with Bmpr2 mutations, 5-lo-expressing neointimal lesions might facilitate vascular inflammation and vascular remodeling (Tian et al. 2019). Pulmonary vascular remodeling is featured by the progress of distinct neointimal lesions, covering concentric laminar intima fibrosis and plexiform lesions (Dickinson et al. 2011). These neointimal lesions give rise to intraluminal obstruction due to EC and SMC proliferation, fibrosis, and inflammation, which ultimately leads to irreversible PAH (Steffes et al. 2020; Chan and Loscalzo 2008). Studies showed that activation of PI3K/Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways mediates LTB 4 through regulating the GSK-3β/β-catenin/cyclin D1 axis to induce PASMCs proliferation, and indicated that this pathway was involved in alleviating vascular remodeling and was beneficial to PAH treatment (Li et al. 2020). The above conclusions proved that the interactions between macrophages and SMCs played an equally significant effect in the pathogenesis and development of PAH.

8 Fibroblasts Crosstalk with Macrophages

Communication mediated by adventitia cells acts a potential role in vascular inflammation and pathogenesis. The adventitia contains many innate immune cells, especially macrophages, fibroblasts, and DCs. The number of fibroblasts accounts for the majority of adventitia cells. The interaction of fibroblasts and macrophages in the adventitia of blood vessels facilitates the transmission of inflammatory signals and the progression of PH (Li et al. 2021). Studies have reported that fibroblasts have the ability to recruit and activate macrophages, leading to vascular inflammation and vascular remodeling, in which lactate and IL-6 play a significant role. Fibroblasts in a large number of animal models and humans with PH regulate macrophage activation (El Kasmi et al. 2014). For example, previous studies have shown that fibroblast paracrine IL-6 and macrophage STAT3 united with hypoxia-inducible factor 1alpha (HIF1α) and CCAAT/enhancer-binding protein beta (C/EBPβ) caused the pathogenesis of PH, which directly led to the occurrence of vascular inflammation and remodeling (El Kasmi et al. 2014). At the same time, studies have found that macrophages can receive and combine the signals sent by fibroblasts and then carry out disparate transcriptomics and metabolomics programming to keep a more stable lung microenvironment during the pathogenesis of PH (Li et al. 2021). LTB4 derived from macrophages aggravated the proliferation, migration, and differentiation of human pulmonary artery adventitia fibroblasts in a dose-dependent manner via its homologous G protein-coupled receptor, BLT1. LTB4 stimulated human pulmonary artery adventitia fibroblasts by up-regulating p38 mitogen-activated protein kinase (MAPK) and NADPH oxidase 4 (Nox4) signaling pathway to promote PH development (Qian et al. 2015). The crosstalks between fibroblasts and macrophages in the microenvironment of the adventitia of blood vessels are expected to play a great therapeutic significance in improving the process of pulmonary vascular remodeling.

9 Concluding Remarks

PH is considered to be a cardiopulmonary disease with pulmonary vascular inflammation, vascular remodeling, and cardiac cell damage (Yeo et al. 2020; Hsu et al. 2020). Cell-to-Cell Crosstalk has been taken as a new and further understanding of the physiology and pathology of PH (Rafikova et al. 2019). Phenotypic changes resulted in pulmonary vascular remodeling, pulmonary vasoconstriction, and pulmonary inflammation contain: (a) the crosstalk between pulmonary ECs and SMCs that generate a lung microenvironment of proliferation, anti-apoptosis, and vasoconstriction (b) the crosstalk between pulmonary ECs and non-SMCs that generate a lung microenvironment of proliferation, anti-apoptosis, and vasoconstriction (c) the crosstalk between AECs and SMCs that cause a lung microenvironment of proliferation, anti-apoptosis, and vasoconstriction (d) the crosstalk between AECs and non-SMCs that create a lung microenvironment of proliferation, anti-apoptosis, and vasoconstriction (e) the crosstalk between macrophages and SMCs to promote a lung microenvironment of proliferation, anti-apoptosis, and vasoconstriction (f) the crosstalk between macrophages and fibroblasts to promote a lung microenvironment of proliferation, anti-apoptosis, and vasoconstriction. As a result, the imbalance between proliferation and apoptosis, between vasoconstriction and vasodilation, as well as proinflammatory and anti-inflammatory resulted in pathological changes in the inner, middle, and adventitia of the pulmonary blood vessels, narrowing of the vascular lumen, vascular remodeling, pulmonary inflammation, and finally increased pulmonary artery pressure.

The morbidity rate of PH is still very high. Some patients are asymptomatic during the onset of the disease, which is the disadvantage of the early diagnosis and treatment (Strauss et al. 2019). The damage and repair of cells and the complex crosstalk between multiple cells have been added to the pathogenesis of PH (Voelkel et al. 2012). If the intricate interactions between vascular cells and their regulatory signaling pathways are enough realized and are applied in clinic, the pathological state of PH can be changed to the greatest extent and the mortality can be reduced. Therefore, the signaling pathways emphasized in the crosstalk between multiple cells play an important role in many diseases, especially PH. It is summarized of the crosstalk between cells in the pathogenesis of PH (Fig. 2).

Fig. 2
figure 2

Cell-to-cell crosstalk in the pathogenesis of PH. The crosstalk between cells (Endothelial cell, Smooth muscle cell, Alveolar Epithelial cell, Fibroblast, Pericyte, and Macrophage) and the regulated signal pathways are involved in the pathogenesis of PH. NF-κB nuclear factor-κB, ET-1 Endothelin-1, BMPR bone morphogenic protein receptor, FoxM1 forkhead box M1, MIF macrophage migration inhibitory factor, BMPR2 bone morphogenic protein receptor 2, HIMF hypoxia-induced mitogenic factor, PDGF-B platelet-derived growth factor-BB, CXCL12 Chemokine 12, HMGB1 high mobility group box-1, 5-HTT Serotonin transporter, MMP-9 matrix metalloproteinase-9, TSP1 The secreted protein thrombospondin-1, IL-6 Interleukin 6, 15-HETE 15-hydroxyeicosatetraenoic acid, PDK4 Pyruvate Dehydrogenase Kinase 4, GM-CSF granulocyte macrophage colony-stimulating factor, CTGF Connective Tissue Growth Factor, LTB4 leukotriene B4, MMP-2 matrix metalloproteinase-2, PFKFB3 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase3, H2O2 hydrogen peroxide, SOD2 superoxide dismutase 2, TNF-α Tumor Necrosis Factor alpha, CXCL8 Chemokine 8, IL-8 Interleukin 8, CXCL1 murine Chemokine 1, NRG1 neuregulin1, TGFα Transforming growth factor alpha, adam17 a disintegrin and metalloproteinase 17, Notch1 notch receptor 1, ERK extracellular signal-regulated kinase, OPN osteopontin, PTEN Phosphatase and tensin homolog, CCR2 C-C chemokine receptor types 2, CCR5 C-C chemokine receptor types 5, PI3K phosphatidylinositol-3-kinase, AKT protein kinase B, FoxO3a Forkhead box protein O3a, Stamp2 Six-transmembrane protein of prostate 2, HIF1α Hypoxia-inducible factor-1 alpha, C/EBPβ CCAAT/enhancer-binding protein beta, JAK2 Janus kinase-2, STAT3 transcription 3, Wnt5a Wnt family member 5A, PS1 presenilin 1, Shh Sonic hedgehog, MiR-143 microRNA-143, ROS reactive oxygen species, miR-92a-3p microRNA-92a-3p, ERK1/2 signal-regulated kinase 1/2, GSK-3β glycogen synthase kinase-3β, p38 MAPK p38 mitogen-activated protein kinases, Nox4 NADPH oxidase 4

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In human and rodents PH, there exist the crosstalks between ECs and SMCs (Lin et al. 2019), ECs and pericytes (Yuan et al. 2019), ECs and Macrophages (Sawada et al. 2014), AECs and fibroblasts (Kato et al. 2014), AECs and macrophages (Hou et al. 2021), macrophages and SMCs (Abid et al. 2019), fibroblasts and macrophages (El Kasmi et al. 2014), ECs and fibroblasts (Labrousse-Arias et al. 2016). However, the crosstalk between AECs and SMCs has been studied only in rodent models until now (Wang et al. 2021). In comparison, the researches in rodent models of PH are more involved in cell-to-cell crosstalk than Human PH disease. And other studies found that in HIMF-induced PH, HMGB1-receptor for advanced glycation end products (RAGE) signal transduction is essential for mediating EC and SMC crosstalk, which was confirmed from idiopathic PH patients and rodent PH. However, data from humanized mice were found to further confirm the clinical significance of the HIMF/HMGB1 signal axis (Lin et al. 2019). Therefore, in future research, humanized mice should be more used in the crosstalk between cells for the development of biomedical research and clinical treatment of PH.

Nowadays, the research focused on network medicine can expand the opportunities for personalized treatment of PH (Wang and Loscalzo 2021). Network medicine is the use of effective genomic instruments as well as biostatistics, bioinformatics, and dynamic system analysis to find the way of the prevention and treatment of PH (Napoli et al. 2019; Fiscon et al. 2018). For instance, in future research, computational modeling techniques can be used to enhance the interpretation of the relationship between the cells on the pulmonary vessels and the pulmonary alveoli, and their interaction with neighboring cells. In conclusion, a full understanding of cell-to-cell crosstalk can bring more therapeutic options to the pathogenesis of PH. The important signals in cell-to-cell crosstalk will become the new targets for the prevention and treatment of PH.